Indole compounds and their use

ABSTRACT

The present disclosure relates to indole compounds and pharmaceutical compositions thereof, and their use in stimulating the immune system of patients in need thereof and in treating cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a national stage application under 35 U.S.C.§ 371 of International Patent Application No. PCT/US2018/061758, filedNov. 19, 2018, which claims priority from U.S. Provisional ApplicationNos. 62/588,751, filed Nov. 20, 2017, and 62/717,387, filed Aug. 10,2018. All of the aforementioned priority applications, are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to indole compounds and their use intreating patients in need thereof, such as patients with cancer or inneed of immune stimulation.

BACKGROUND OF THE INVENTION

The aryl hydrocarbon (Ah) receptor (AhR) is a ligand-inducibletranscription factor and a member of the basichelix-loop-helix/Per-Arnt-Sim (bHLH/PAS) superfamily. Upon binding toits ligand, AhR mediates a series of biological processes, includingcell division, apoptosis, cell differentiation, adipose differentiation,hypothalamus actions, angiogenesis, immune system modulation,teratogenicity, tumorigenicity, tumor progression, chloracne, wasting,actions of hormonal systems (e.g., estrogen and androgen), andexpression of genes of the P450 family (Poland et al., Annu. Rev.Pharmacol. Toxicol. 22:517-554 (1982); Poellinger et al., Food AdditContam. 17(4):261-6 (2000); Bock et al., Biochem. Pharmacol.69(10):1403-1408 (2005); Stevens et al., Immunology 127(3):299-311(2009); Puga et al., Biochem Pharmacol. 69(2):199-207 (2005); Safe etal., Int J Oncol. 20(6):1123-8 (2002); Dietrich et al., Carcinogenesis31(8):1319-1328 (2010); U.S. Pat. No. 7,419,992). The liganded receptorparticipates in biological processes through translocation fromcytoplasm into the nucleus, heterodimerization with another factor namedAh receptor nuclear translocator, and binding of the heterodimer to theAh response element of AhR-regulated genes, resulting in enhancement orinhibition of transcription of those genes.

The AhR is able to bind, with different affinities, to several groups ofexogenous chemicals, or artificial ligands, including polycyclicaromatic hydrocarbons, e.g., 3-methylcholanthrene (3-MC), andhalogenated aromatic hydrocarbons, e.g.,2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Studies with those AhRartificial ligands have helped in advancing the understanding of the AhRsystem. An endogenous or physiological ligand for the AhR has beenidentified as 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acidmethyl ester (ITE), with the following structure:

See, e.g., Song et al., PNAS USA 99(23):14694-9 (2002); and U.S. Pat.No. 6,916,834.

SUMMARY OF THE INVENTION

The present disclosure provides novel indole compounds useful inmodulating an activity of human aryl hydrocarbon receptor (AhR),pharmaceutical compositions comprising one or more of these compounds,use of these compounds and compositions in treating diseases andconditions in patients who can benefit from modulation of AhRactivities.

Provided herein is a compound having the structure of formula 2, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is N(nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N (nitrogen), O(oxygen), S (sulfur) or C (carbon); and X₄ is N (nitrogen) O (oxygen), S(sulfur), or C (carbon), such that at least one of X₁, X₂, X₃ and X₄ isN, each of X₁, X₂, X₃ and X₄ is optionally selected to form aheteroaromatic, wherein the bond between X₁ and the adjacent carbon,between X₂ and the adjacent carbon, between X₁ and X₄, between X₂ andX₃, and between X₃ and X₄ can be a single bond or a double bond and thevalence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl (i.e.,the ring can be aromatic, partially saturated, or saturated);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₂ and R₃ are together selected from the group consisting of ═O, ═S, or═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H, C₁-C₆alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is directlyconnected to S), wherein R₁₀ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from thegroup consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, R₂ preferably can be ═O, R₃ preferably can be —OR, wherein Ris H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂ preferably can be ═O,R₃ preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂ and R₃preferably can be each independently —OR or —NR_(a)R_(b), wherein R,R_(a), and R_(b) are each independently H, C₁-C₆ alkyl, or C₁-C₆ acyl,or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Also provided herein is a compound having the structure of formula 2a,or an enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

X is either O (oxygen) or S (sulfur);

Z is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₂ and R₃ are together selected from the group consisting of ═O, ═S, or═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H, C₁-C₆alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is directlyconnected to S), wherein R₁₀ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from thegroup consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, R₂ preferably can be ═O, R₃ preferably can be —OR, wherein Ris H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂ preferably can be ═O,R₃ preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂ and R₃preferably can be each independently —OR or —NR_(a)R_(b), wherein R,R_(a), and R_(b) are each independently H, C₁-C₆ alkyl, or C₁-C₆ acyl,or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Also provided herein is a compound having the structure of formula 3, oran enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is N(nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N (nitrogen), O(oxygen), S (sulfur) or C (carbon); and X₄ is N (nitrogen) O (oxygen), S(sulfur), or C (carbon), such that at least one of X₁, X₂, X₃ and X₄ isN, each of X₁, X₂, X₃ and X₄ is optionally selected to form aheteroaromatic, wherein the bond between X₁ and the adjacent carbon,between X₂ and the adjacent carbon, between X₁ and X₄, between X₂ andX₃, and between X₃ and X₄ can be a single bond or a double bond and thevalence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl (i.e.,the ring can be aromatic, partially saturated, or saturated);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Further provided herein is a compound having the structure of formula3a, or an enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

X is either O (oxygen) or S (sulfur);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Provided further herein is a compound having the structure of formula3b, or an enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

X is either O (oxygen) or S (sulfur);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Provided herein is also a compound having the structure of formula 3c,or an enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is N(nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N (nitrogen), O(oxygen), S (sulfur) or C (carbon); and X₄ is N (nitrogen) O (oxygen), S(sulfur), or C (carbon), such that at least one of X₁, X₂, X₃ and X₄ isN, each of X₁, X₂, X₃ and X₄ is optionally selected to form aheteroaromatic, wherein the bond between X₁ and the adjacent carbon,between X₂ and the adjacent carbon, between X₁ and X₄, between X₂ andX₃, and between X₃ and X₄ can be a single bond or a double bond and thevalence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl (i.e.,the ring can be aromatic, partially saturated, or saturated);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andare each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl), thioalkoxy(—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Also provided herein is a compound having the structure of formula 4, oran enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

X is O (oxygen) or S (sulfur);

Y is a bond, O (oxygen), S (sulfur), or

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from thegroup consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is directlyconnected to S), wherein R₁₀ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl;

R₂ and R₃ are together selected from the group consisting of ═O, ═S, or═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H, C₁-C₆alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Further provided herein is a compound having the structure of formula 5,or an enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

X is O (oxygen) or S (sulfur);

Y is a bond, O (oxygen), S (sulfur), or

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

Also provided herein is a compound having the structure of formula 6, oran enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₄ (n=0 to 2, R₁₄ is directly connected to S), wherein R₁₄ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio;

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl;

B₁, B₂, B₃, B₄, B₅, and B₆ are each independently C or N;

R₉ and R₁₀, the number of which, together, complete the valence of eachof B₁, B₂, B₃, B₄, B₅, and B₆, are each independently selected from thegroup consisting of hydrogen, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b),—(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b),—(C₀-C₆ alkyl)-SO₂NHCOR_(2a), —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₂ (n=0 to 2, R₁₂is directly connected to S), wherein R₁₂ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and

wherein R_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

wherein R₂ and R₃ are together selected from the group consisting of ═O,═S, or ═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H,C₁-C₆ alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₃ (n=0 to 2, R₁₃ is directlyconnected to S), wherein R₁₃ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In some embodiments, the invention provides a compound having thestructure of formula 7, or an enantiomer, diastereomer, orpharmaceutically acceptable salt thereof:

wherein:

Y is a bond, O (oxygen), S (sulfur), or

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl;

B₁, B₂, B₃, B₄, B₅, and B₆ are each independently C or N;

R₉ and R₁₀, the number of which, together, complete the valence of eachof B₁, B₂, B₃, B₄, B₅, and B₆, are each independently selected from thegroup consisting of hydrogen, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b),—(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b),—(C₀-C₆ alkyl)-SO₂NHCOR_(2a), —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₂ (n=0 to 2, R₁₂is directly connected to S), wherein R₁₂ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and

wherein R_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

wherein R₂ and R₃ are together selected from the group consisting of ═O,═S, or ═NR_(a)(R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H,C₁-C₆ alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₃ (n=0 to 2, R₁₃ is directlyconnected to S), wherein R₁₃ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In each of formulae 2, 2a, 3, 3a, 3b, 3c, 4 and 5, in some embodiments,each of R₄, R₅, R₆, and R₇ is hydrogen. In other embodiments, at leastone of R₄, R₅, R₆, and R₇ can be F, Cl or Br, and the others of R₄, R₅,R₆, and R₇ are hydrogen. In still other embodiments, at least two of R₄,R₅, R₆, and R₇, independently, can be F, Cl or Br, and the others of R₄,R₅, R₆, and R₇ are hydrogen. The F, Cl or Br can be at the indole ringcarbon 5, 6, or 7.

In each of formulae 3, 3a, 3b, 3c, and 5, in certain embodiments, R₉ canbe hydrogen. R₂ can be acyl, cyano, hydroxyl-substituted C1-C6 alkyl,amino-substituted C1-C6 alkyl, aryl, or heteroaryl. The aryl orheteroaryl can be substituted or unsubstituted. The substituted aryl orheteroaryl can be substituted with halo, amino, hydroxyl, or C1-C6alkyl. The amino can be unsubstituted.

In each of formulae 2, 2a, and 4, in certain embodiments, R₂ can behydroxyl or amino and R₃ can be alkyl, aryl, nitro, or cyano. R₉ can behydrogen. The amino can be substituted or unsubstituted.

In some embodiments, the invention provides a compound having thestructure of formula 8, or an enantiomer, diastereomer, orpharmaceutically acceptable salt thereof:

wherein R₂ is selected from the group consisting of substituted alkyl,heteroaryl, or

wherein R_(2a) is H, C1-C6 alkyl, alkoxy (—O-alkyl), hydroxy, thioalkoxy(—S-alkyl), cyano (—CN), or amino; and

R₄, R₅, R₆, and R₇, are each independently selected from the groupconsisting of hydrogen and halo.

In some embodiments, R₂ is substituted alkyl, e.g., a C1-C6 alkylsubstituted with one or more hydroxyl, amino, nitro, or cyano. In someembodiments, R₂ is heteroaryl, e.g., oxadiazolyl or thiadiazolyl,optionally substituted with one or more hydroxyl, amino, nitro, cyano,C1-C6 alkyl, or C1-C6 alkyl amino. In some embodiments, R₂ is—C(O)—R_(2a), and R_(2a) is C1-C6 alkyl.

In one embodiment of the compound of structural formula 8, at least oneof R₄, R₅, R₆, and R₇ is F, Cl or Br, and the others of R₄, R₅, R₆, andR₇ are hydrogen. In another embodiment, at least two of R₄, R₅, R₆, andR₇ are F, Cl or Br, and the others of R₄, R₅, R₆, and R₇ are hydrogen.

In one embodiment, R₅ is F, and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is F, and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is F, and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ is Cl, and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is Cl, and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is Cl, and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ and R₆ are F, and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are F, and R₄ and R₆ are hydrogen. Instill another embodiment, R₆ and R₇ are F, and R₄ and R₅ are hydrogen.

In one embodiment, R₅ and R₆ are Cl, and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are Cl, and R₄ and R₆ are hydrogen. Instill another embodiment, R₆ and R₇ are Cl, and R₄ and R₅ are hydrogen.

In some embodiments, each of R₄, R₅, R₆ and R₇ is hydrogen.

In some embodiments, the present disclosure provides a compound selectedfrom a compound in Table 1 (e.g., ARI-017, ARI-018, ARI-019, ARI-020,ARI-031, ARI-060, ARI-083, ARI-087, ARI-090, ARI-118, ARI-120, ARI-140,ARI-143, ARI-145, ARI-146, ARI-148, ARI-149, or ARI-150), or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof.In some embodiments, the present disclosure provides a compound selectedfrom ART-087, ARI-140, ARI-143, ARI-149, and ARI-150, or an enantiomer,diastereomer, or pharmaceutically acceptable salt thereof. In someembodiments, the present disclosure provides a compound selected fromARI-031, ARI-060, ARI-083, ARI-090, ARI-118, ARI-120, ARI-145, ARI-146,and ARI-148, or an enantiomer, diastereomer, or pharmaceuticallyacceptable salt thereof.

The present disclosure also provides a pharmaceutical compositioncomprising a compound described herein and a pharmaceutically acceptablecarrier.

The present disclosure provides a method of stimulating the immunesystem in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound describedherein. In some embodiments, the patient has an increased count of cellsselected from the group consisting of white blood cells, macrophages,neutrophils, lymphocytes (e.g., B lymphocytes and/or T lymphocytes),natural killer (NK) cells, dendritic cells, and platelets, or increasedlevels of cytokines indicative of a stimulated immune system after theadministering step. In some embodiments, the compound decreases IL-21level in the patient. In some embodiments, the patient has cancer.

The present disclosure also provides a method of treating cancer in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound described herein. In some embodiments,the cancer is a hematological malignancy (e.g., a lymphoma, leukemia, ormyeloma), or a solid tumor. In some embodiments, the cancer may beselected from the group consisting of diffuse large B-cell lymphoma,marginal zone lymphoma, chronic lymphocytic leukemia (CLL), smalllymphocytic lymphoma, prolymphocytic leukemia, acute lymphocyticleukemia, Waldenström's Macroglobulinemia (WM), follicular lymphoma,mantle cell lymphoma (MCL), Hodgkin lymphoma, non-Hodgkin lymphoma,multiple myeloma, prostate cancer, ovarian cancer, fallopian tubecancer, cervical cancer, breast cancer, lung cancer (e.g., non-smallcell lung cancer), skin cancer (e.g., melanoma), colorectal cancer,stomach cancer, pancreatic cancer, liver cancer, kidney cancer, bladdercancer, soft tissue cancer, glioma, and head and neck cancer. In someembodiments, the method further comprises administering to the patientanother cancer therapeutic agent, e.g., an immune checkpoint inhibitor(e.g., a PD-1, PD-L1, and/or PD-L2 inhibitor). In some embodiments, themethod further comprises administering one or more maintenance doses ofthe compound while the patient is in remission.

Also provided herein is a compound or pharmaceutical compositiondescribed herein for use in stimulating the immune system or treatingcancer in a patient in need thereof in a treatment method describedherein.

The present disclosure further provides the use of a compound describedherein for the manufacture of a medicament for stimulating the immunesystem or treating cancer in a patient in need thereof in a treatmentmethod described herein.

The present disclosure also provides articles of manufacture, includingkits, that comprise a compound described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a synthesis scheme for substituted indoles intermediates.

FIG. 2 shows a synthesis scheme for esters and amides.

FIG. 3 shows a synthesis scheme for nitriles.

FIG. 4 shows a synthesis scheme for ketones.

FIG. 5 shows a first synthesis scheme for heterocycle.

FIG. 6 shows a second synthesis scheme for heterocycle.

FIG. 7 shows a third synthesis scheme for heterocycle.

FIG. 8 shows a fourth synthesis scheme for heterocycle.

FIG. 9 shows a fifth synthesis scheme for heterocycle.

FIG. 10 shows a sixth synthesis scheme for heterocycle.

FIG. 11 shows a seventh synthesis scheme for heterocycle.

FIG. 12 shows an eighth synthesis scheme for heterocycle.

FIG. 13 shows a synthesis scheme for CF₃ ketone.

FIG. 14 shows a synthesis scheme for CF₃ amine.

FIG. 15 shows a synthesis scheme for α-aminonitrile.

FIG. 16 shows a scheme for preparing the key intermediates Int-A, Int-Band Int-C.

FIG. 17 shows a scheme for preparing the key intermediate Int-E.

FIG. 18 shows a synthesis scheme for ARI-064 according to Example 43.

FIG. 19 shows a synthesis scheme for ARI-075 according to Example 48.

FIG. 20 shows a synthesis scheme for ARI-121 according to Example 64.

FIG. 21 shows a synthesis scheme for ARI-041 (PTC17341-17) according toExample 65.

FIG. 22 shows a synthesis scheme for ARI-049 (PTC17341-06) according toExample 68.

FIG. 23 shows a synthesis scheme for ARI-058 (PTC17341-05) according toExample 71.

FIG. 24 shows a synthesis scheme for ARI-077 according to Example 75.

FIG. 25 shows a synthesis scheme for ARI-068 (PTC17341-16), ARI-092(PTC17341-16A), and ARI-094 (PTC17341-16B) according to Example 77.

FIG. 26 shows a synthesis scheme for ARI-069 and ARI-070 (PTC17341-22-Aand PTC17341-22-B) according to Example 78.

FIG. 27 shows a synthesis scheme for ARI-085 (PTC17341-46) according toExample 82.

FIG. 28 shows a synthesis scheme for ARI-086 (PTC17341-35) according toExample 83.

FIG. 29 shows a synthesis scheme for ARI-087 according to Example 84.

FIG. 30 shows a synthesis scheme for PTC17341-11A according to Example87.

FIG. 31 shows a synthesis scheme for ARI-123 (PTC17341-95) according toExample 102.

FIG. 32 shows a synthesis scheme for ARI-127 (PTC17341-54) according toExample 106.

FIG. 33 shows a synthesis scheme for ARI-137 (PTC17341-108) according toExample 114.

FIG. 34 shows a synthesis scheme for ARI-138 (PTC17341-107) according toExample 115.

FIG. 35 shows a synthesis scheme for ARI-139 (PTC17341-109) according toExample 116.

FIG. 36 shows a synthesis scheme for ARI-141 (PTC17341-60) according toExample 118.

FIG. 37 shows a synthesis scheme for ARI-149 according to Example 125.

FIG. 38 shows a synthesis scheme for ARI-054 (PTC17341-21) according toExample 127.

FIG. 39 shows a synthesis scheme for ARI-150 according to Example 129.

FIG. 40 shows a synthesis scheme for2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl) thiazole-4-carboxylicacid according to Example 130.

FIG. 41 shows a synthesis scheme for ARI-154 according to Example 131.

FIG. 42 shows a scheme of synthesizing dibromo compounds according toExample 135.

FIG. 43 shows exemplary compounds where thiazole and ester fragments aremodified to potentially slow ester hydrolysis according to Example 136.

FIG. 44 describes a route of synthesis for ARI-1073 and ARI-024according to Example 137.

FIG. 45 illustrates a synthesis route for ARI-068, ARI-092, and ARI-094according to Example 138.

FIG. 46 illustrates a synthesis route for ARI-1029 and ARI-1030according to Example 139.

FIG. 47 illustrates a synthesis route for amino amides and cyclicversions of compounds according to Example 140.

FIG. 48 illustrates a synthesis route for oxime compounds with hinderedketones according to Example 141.

FIG. 49 illustrates a synthesis route for pyrazine compounds accordingto Example 142.

FIG. 50 compares the properties of compounds with thiazole and indolereplacements according to Example 143.

FIG. 51 shows a synthesis scheme for ARI-020 according to Example 144.

FIG. 52 shows a synthesis scheme for ARI-018 according to Example 145.

FIG. 53 shows a synthesis scheme for ARI-019 according to Example 146.

FIG. 54 shows a synthesis scheme for ARI-017 according to Example 147.

FIG. 55 shows a synthesis scheme for ARI-030 according to Example 148.

FIG. 56 shows a synthesis scheme for an aldehyde intermediate accordingto Example 149.

FIG. 57 shows a synthesis scheme for ARI-021 according to Example 150.

FIG. 58 shows a synthesis scheme for ARI-1057 according to Example 151.

FIG. 59 shows a synthesis scheme for hindered ketones.

FIGS. 60A-D are graphs showing the tumor inhibitory activity of ARI-002and ARI-087 in the indicated syngeneic mouse tumor models. A: EMT-6. B:Pan02. C: A20. D: LL/2. IP: intraperitoneal injection. Vehicle control:DMSO.

FIG. 61 is a graph comparing the tumor inhibitory activities of ARI-087and ARI-140 in the EMT-6 syngeneic mouse tumor model.

FIG. 62 is a graph comparing the tumor inhibitory activities of ARI-087and ARI-149 in the EMT-6 syngeneic mouse tumor model.

FIG. 63 is a graph comparing the tumor inhibitory activities of ARI-087and ARI-143 in the EMT-6 syngeneic mouse tumor model.

FIG. 64 is a graph comparing the tumor inhibitory activities of ARI-087and ARI-118 in the EMT-6 syngeneic mouse tumor model.

DETAILED DESCRIPTION OF THE INVENTION

All technical and scientific terms used herein are the same as thosecommonly used by those ordinary skilled in the art to which the presentinvention pertains unless defined specifically otherwise.

The moieties described below can be substituted or unsubstituted.“Substituted” refers to replacement of a hydrogen atom of a molecule oran R-group with one or more additional R-groups such as halogen, alkyl,haloalkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, trifluoromethyl,acyloxy, hydroxy, hydroxyalkyl, mercapto, carboxy, cyano, acyl, aryloxy,aryl, arylalkyl, heteroaryl, amino, aminoalkyl, alkylamino,dialkylamino, morpholino, piperidino, pyrrolidin-1-yl, piperazin-1-yl,nitro, phosphine, phosphinate, phosphonate, sulfato, ═O, ═S, or otherR-groups. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of a group.Combinations of substituents contemplated herein are preferably thosethat result in the formation of stable (e.g., not substantially alteredfor a week or longer when kept at a temperature of 40° C. or lower inthe absence of moisture or other chemically reactive conditions), orchemically feasible, compounds.

“Hydroxy”, “thiol”, “cyano”, “nitro”, and “formyl” refer, respectively,to —OH, —SH, —CN, —NO₂, and —CHO.

“Acyloxy” refers to a RC(═O)O— radical, wherein R is alkyl, cycloalkyl,aryl, heteroalkyl, heteroaryl, or heterocycloalkyl, which are asdescribed herein. In some embodiments, it is a C₁-C₄ acyloxy radical,which refers to the total number of chain or ring atoms of the alkyl,cycloalkyl, aryl, heteroalkyl, heteroaryl, or heterocycloalkyl portionof the acyloxy group plus the carbonyl carbon of acyl, i.e., the otherring or chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms.

“Alkyl” refers to a group of 1-18, 1-16, 1-12, 1-10, preferably 1-8,more preferably 1-6 unsubstituted or substituted hydrogen-saturatedcarbons connected in linear, branched, or cyclic fashion, including thecombination in linear, branched, and cyclic connectivity. Non-limitingexamples include methyl, ethyl, propyl, isopropyl, butyl, and pentyl.

“Cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radicalthat contains carbon and hydrogen, and may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms (e.g., C₃-C₁₀ cycloalkyl). Whenever it appears herein, a numericalrange such as “3 to 10” refers to each integer in the given range; e.g.,“3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3carbon ring atoms, 4 carbon ring atoms, 5 carbon ring atoms, etc., up toand including 10 carbon ring atoms. In some embodiments, it is a C₃-C₈cycloalkyl radical. In some embodiments, it is a C₃-C₅ cycloalkylradical. Examples of cycloalkyl group include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, andnorbornyl. The term “cycloalkyl” also refers to spiral ring system, inwhich the cycloalkyl rings share one carbon atom.

“Heterocycloalkyl” refers to a 3- to 18-membered nonaromatic ring (e.g.,C₃-C₁₈ heterocycloalkyl) radical that comprises two to twelve ringcarbon atoms and from one to six heteroatoms selected from nitrogen,oxygen and sulfur. Whenever it appears herein, a numerical range such as“3 to 18” refers to each integer in the given range; e.g., “3 to 18 ringatoms” means that the heterocycloalkyl group may consist of 3 ringatoms, 4 ring atoms, etc., up to and including 18 ring atoms. In someembodiments, it is a C₅-C₁₀ heterocycloalkyl. In some embodiments, it isa C₄-C₁₀ heterocycloalkyl. In some embodiments, it is a C₃-C₁₀heterocycloalkyl. The heterocycloalkyl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fusedor bridged ring systems. The heteroatoms in the heterocycloalkyl radicalmay be optionally oxidized. One or more nitrogen atoms, if present, mayoptionally be quaternized. The heterocycloalkyl radical may be partiallyor fully saturated. The heterocycloalkyl may be attached to the rest ofthe molecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to,6,7-dihydro-5H-cyclopenta[b]pyridine, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In someembodiments, the heterocycloalkyl group is aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl,tetrahydroquinolyl, tetrahydroisoquinolin and benzoxazinyl, preferablydihydrooxazolyl and tetrahydrofuranyl.

“Halo” refers to any of halogen atoms fluorine (F), chlorine (Cl),bromine (Br), or iodine (I). A particular example of such halo groups isfluorine.

“Haloalkyl” refers to an alkyl substituted by one or more halo(s).

“Alkenyl” refers to a group of unsubstituted or substituted hydrocarbonscontaining 2-18, 2-16, 2-12, 2-10, for example, 2-8 (e.g., 2-6) carbons,which are linear, branched, cyclic, or in combination thereof, with atleast one carbon-to-carbon double bond.

“Haloalkenyl” refers to an alkenyl substituted by one or more halo(s).

“Alkynyl” refers to a group of unsubstituted or substituted hydrocarbonscontaining 2-18, 2-16, 2-12, 2-10, for example, 2-8 (e.g., 2-6) carbons,which are linear, branched, cyclic, or in combination thereof, with atleast one carbon-to-carbon triple bond.

“Haloalkynyl” refers to an alkynyl substituted by one or more halo(s).

“Amino protecting group” refers to those groups intended to protect anamino group against undesirable reactions during synthetic proceduresand which can later be removed to reveal the amine. Commonly used aminoprotecting groups are disclosed in Protective Groups in OrganicSynthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York,N.Y., (3rd Edition, 1999). Amino protecting groups include acyl groupssuch as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,o-nitrophenoxyacetyl, alpha-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- oraryloxy-carbonyl groups (which form urethanes with the protected amine)such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,alpha,alpha-dimethyl-3,5-dimethoxybenzyloxycarbonyl,benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,methoxycarbonyl, allyloxycarbonyl (Alloc),2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc),phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl(Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl,cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groupssuch as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silylgroups such as trimethylsilyl and the like. Amine protecting groups alsoinclude cyclic amino protecting groups such as phthaloyl anddithiosuccinimidyl, which incorporate the amino nitrogen into aheterocycle. Typically, amino protecting groups include formyl, acetyl,benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl,Fmoc, Boc and Cbz.

“Amino” refers to unsubstituted amino and substituted amino groups, forexample, primary amines, secondary amines, tertiary amines andquaternary amines. Specifically, “amino” refers to —NR_(a)R_(b), whereinR_(a) and R_(b), both directly connected to the N, can be independentlyselected from hydrogen, deuterium, halo, hydroxy, cyano, formyl, nitro,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, a nitrogen protective group,—(CO)-alkyl, —(CO)—O-alkyl, or —S(O)_(n)R_(c) (n=0 to 2, R_(c) isdirectly connected to S), wherein R_(c) is independently selected fromhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, or halothiocarbonylthio.

“Aryl” refers to a C₆-C₁₄ aromatic hydrocarbon. For example, aryl can bephenyl, napthyl, or fluorenyl.

“Heteroaryl” refers to a C₆-C₁₄ aromatic hydrocarbon having one or moreheteroatoms, such as N, O or S. The heteroaryl can be substituted orunsubstituted. Examples of a heteroaryl include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl,benzofurazanyl, benzothiazolyl, benzothienyl,benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). In some embodiments, the heteroaryl can be dithiazinyl, furyl,imidazolyl, indolyl, isoquinolinyl, isoxazolyl, oxadiazolyl (e.g.,(1,3,4)-oxadiazolyl, or (1,2,4)-oxadiazolyl), oxazolyl, pyrazinyl,pyrazolyl, pyrazyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl,pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazinyl,(1,2,3)-triazolyl, (1,2,4)-triazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl,5-amino-1,2,4-oxadiazolyl, 5-amino-1,3,4-oxadiazolyl,5-amino-1,3,4-oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl,5-methyl-1,2,4-oxadiazolyl, 5-(trifluoromethyl)-1,2,4-oxadiazolyl,5-(methylamino)-1,2,4-oxadiazolyl, 5-(aminomethyl)-1,2,4-oxadiazolyl,5-(aminomethyl)-1,3,4-oxadiazolyl, 5-amino-4-cyanooxazolyl,5,6-dichloro-1H-indolyl, 5,6-difluoro-1H-indolyl, 5-chloro-1H-indolyl,5,6-dibromo-1H-indolyl, 5-fluoro-1H-indolyl, 5-methoxy-1H-indolyl,7-fluoro-1H-indolyl, 6-cyano-1H-indolyl, 5-cyano-1H-indolyl,4-fluoro-1H-indolyl, 5,6-difluoro-1H-indolyl, 6-fluoro-1H-indolyl, or5,7-difluoro-1h-indolyl.

The substituent on the heteroaryl group can be alkyl (e.g., C1-C6alkyl), amino, cyano, halo (e.g., fluoro, bromo, and chloro), alkylamino(e.g., C1-C6 alkylamino), methyleneamino, nitro, or hydroxyl. Theheteroaryl group can have two, three or four substituents.

“Carbocycle” refers to a C₆-C₁₄ cyclic hydrocarbon. For example, arylcan be phenyl, napthyl, or fluorenyl.

“Heterocycle” refers to a C₆-C₁₄ cyclic hydrocarbon having one or moreheteroatoms, such as N, O or S.

“Alkoxy” refers to an alkyl connected to an oxygen atom (—O— alkyl).

“Haloalkoxy” refers to a haloalkyl connected to an oxygen atom (—O—haloalkyl).

“Thioalkoxy” refers to an alkyl connected to a sulfur atom (—S— alkyl).

“Halothioalkoxy” refers to a haloalkyl connected to a sulfur atom (—S—haloalkyl).

“Carbonyl” refers to —(CO)—, wherein (CO) indicates that the oxygen isconnected to the carbon with a double bond.

“Alkanoyl” or “acyl” refers to an alkyl connected to a carbonyl group[—(CO)— alkyl].

“Haloalkanoyl” or “haloacyl” refers to a haloalkyl connected to acarbonyl group [—(CO)— haloalkyl].

“Thiocarbonyl” refers to —(CS)—, wherein (CS) indicates that the sulfuris connected to the carbon with a double bond.

“Thioalkanoyl (or thioacyl)” refers to an alkyl connected to athiocarbonyl group [—(CS)— alkyl].

“Halothioalkanoyl” or “halothioacyl” refers to a haloalkyl connected toa thiocarbonyl group [—(CS)— haloalkyl].

“Carbonyloxy” refers to an alkanoyl (or acyl) connected to an oxygenatom [—O—(CO)— alkyl].

“Halocarbonyloxy” refers to a haloalkanoyl (or haloacyl) connected to anoxygen atom [—O—(CO)— haloalkyl].

“Carbonylthio” refers to an alkanoyl (or acyl) connected to a sulfuratom [—S—(CO)— alkyl].

“Halocarbonylthio” refers to a haloalkanoyl (or haloacyl) connected to asulfur atom [—S—(CO)— haloalkyl].

“Thiocarbonyloxy” refers to a thioalkanoyl (or thioacyl) connected to anoxygen atom [—O—(CS)— alkyl].

“Halothiocarbonyloxy” refers to a halothioalkanoyl (or halothioacyl)connected to an oxygen atom [—O—(CS)— haloalkyl].

“Thiocarbonylthio” refers to a thioalkanoyl (or thioacyl) connected to asulfur atom [—S—(CS)— alkyl].

“Halothiocarbonylthio” refers to a halothioalkanoyl (or halothioacyl)connected to a sulfur atom [—S—(CS)— haloalkyl].

Indole Compounds

An aspect of the present disclosure relates to novel indole compoundsthat can modulate human aryl hydrocarbon receptor (AhR). These compoundsbind specifically to AhR. Without wishing to be bound by theory, it iscontemplated that AhR bound by one of the present compounds is agonizedwith respect to the receptor's immune-stimulatory activity.

In some embodiments, the compound has the structure of formula 2, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is N(nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N (nitrogen), O(oxygen), S (sulfur) or C (carbon); and X₄ is N (nitrogen) O (oxygen), S(sulfur), or C (carbon), such that at least one of X₁, X₂, X₃ and X₄ isN, each of X₁, X₂, X₃ and X₄ is optionally selected to form aheteroaromatic, wherein the bond between X₁ and the adjacent carbon,between X₂ and the adjacent carbon, between X₁ and X₄, between X₂ andX₃, and between X₃ and X₄ can be a single bond or a double bond and thevalence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl (i.e.,the ring can be aromatic, partially saturated, or saturated);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₂ and R₃ are together selected from the group consisting of ═O, ═S, or═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H, C₁-C₆alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is directlyconnected to S), wherein R₁₀ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from thegroup consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, R₂ preferably can be ═O, R₃ preferably can be —OR, wherein Ris H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂ preferably can be ═O,R₃ preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂ and R₃preferably can be each independently —OR or —NR_(a)R_(b), wherein R,R_(a), and R_(b) are each independently H, C₁-C₆ alkyl, or C₁-C₆ acyl,or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, Z₁ is CR₄, Z₂ is CR₅, Z₃ is CR₆, Z₄ is CR₇, Z₅is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo, cyano, formyl, or nitroand each of R₅, R₆, R₇, and R₈ is H. In certain embodiments, at leastone of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl or Br.

In some embodiments, the compound has the structure of formula 2a, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X is either O (oxygen) or S (sulfur);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₂ and R₃ are together selected from the group consisting of ═O, ═S, or═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H, C₁-C₆alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is directlyconnected to S), wherein R₁₀ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from thegroup consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, R₂ preferably can be ═O, R₃ preferably can be —OR, wherein Ris H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂ preferably can be ═O,R₃ preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂ and R₃preferably can be each independently —OR or —NR_(a)R_(b), wherein R,R_(a), and R_(b) are each independently H, C₁-C₆ alkyl, or C₁-C₆ acyl,or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, the carbon-carbon double bond of thefive-membered nitrogen-containing ring can be saturated. The compoundsdescribed herein include stereoisomers or diastereomers of the saturatedcarbon atoms. The saturation can be hydrogen or C₁-C₆ alkyl groups addedto the carbon-carbon bond. In certain embodiments, Z₁ is CR₄, Z₂ is CR₅,Z₃ is CR₆, Z₄ is CR₇, Z₅ is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo,cyano, formyl, or nitro and each of R₅, R₆, R₇, and R₈ is H. In certainembodiments, at least one of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl orBr.

In some embodiments, the compound has the structure of formula 3, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is N(nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N (nitrogen), O(oxygen), S (sulfur) or C (carbon); and X₄ is N (nitrogen) O (oxygen), S(sulfur), or C (carbon), such that at least one of X₁, X₂, X₃ and X₄ isN, each of X₁, X₂, X₃ and X₄ is optionally selected to form aheteroaromatic, wherein the bond between X₁ and the adjacent carbon,between X₂ and the adjacent carbon, between X₁ and X₄, between X₂ andX₃, and between X₃ and X₄ can be a single bond or a double bond and thevalence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl (i.e.,the ring can be aromatic, partially saturated, or saturated);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio,

wherein R_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, Z₁ is CR₄, Z₂ is CR₅, Z₃ is CR₆, Z₄ is CR₇, Z₅is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo, cyano, formyl, or nitroand each of R₅, R₆, R₇, and R₈ is H. In certain embodiments, at leastone of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl or Br. In certainembodiments, R_(2a) is substituted amino. Substituted amino can includealkyl amino, for example, unsubstituted alkylamino, hydroxyalkylamino oralkoxyalkylamino, or cycloalkyl amino, for example, —NR_(a)R_(b) whereR_(a) and R_(b) together form a 3, 4, 5, 6, 7, or 8 member alkylenering. The alkylene ring can be unsubstituted or substituted, forexample, with halo, hydroxyl, alkoxy, or alkyl (including substitutedalkyl) groups.

In some embodiments, the compound has the structure of formula 3c, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is N(nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N (nitrogen), O(oxygen), S (sulfur) or C (carbon); and X₄ is N (nitrogen) O (oxygen), S(sulfur), or C (carbon), such that at least one of X₁, X₂, X₃ and X₄ isN, each of X₁, X₂, X₃ and X₄ is optionally selected to form aheteroaromatic, wherein the bond between X₁ and the adjacent carbon,between X₂ and the adjacent carbon, between X₁ and X₄, between X₂ andX₃, and between X₃ and X₄ can be a single bond or a double bond and thevalence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl (i.e.,the ring can be aromatic, partially saturated, or saturated);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, Z₁ is CR₄, Z₂ is CR₅, Z₃ is CR₆, Z₄ is CR₇, Z₅is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo, cyano, formyl, or nitroand each of R₅, R₆, R₇, and R₈ is H. In certain embodiments, at leastone of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl or Br. In certainembodiments, R_(2a) is substituted amino. Substituted amino can includealkyl amino, for example, unsubstituted alkylamino, hydroxyalkylamino oralkoxyalkylamino, or cycloalkyl amino, for example, —NR_(a)R_(b) whereR_(a) and R_(b) together form a 3, 4, 5, 6, 7, or 8 member alkylenering. The alkylene ring can be unsubstituted or substituted, forexample, with halo, hydroxyl, alkoxy, or alkyl (including substitutedalkyl) groups.

In some embodiments, the compound has the structure of formula 3a, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X is either O (oxygen) or S (sulfur);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl; or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, the carbon-carbon double bond of thefive-membered nitrogen-containing ring can be saturated. The compoundsdescribed herein include stereoisomers or diastereomers of the saturatedcarbon atoms. The saturation can be hydrogen or C₁-C₆ alkyl groups addedto the carbon-carbon bond. In certain embodiments, Z₁ is CR₄, Z₂ is CR₅,Z₃ is CR₆, Z₄ is CR₇, Z₅ is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo,cyano, formyl, or nitro and each of R₅, R₆, R₇, and R₈ is H. In certainembodiments, R_(2a) is substituted amino. Substituted amino can includealkyl amino, for example, unsubstituted alkylamino, hydroxyalkylamino oralkoxyalkylamino, or cycloalkyl amino, for example, —NR_(a)R_(b) whereR_(a) and R_(b) together form a 3, 4, 5, 6, 7, or 8 member alkylenering. The alkylene ring can be unsubstituted or substituted, forexample, with halo, hydroxyl, alkoxy, or alkyl (including substitutedalkyl) groups. In certain embodiments, at least one of R₄, R₅, R₆, andR₇ is halo, e.g., F, Cl or Br.

In some embodiments, the compound has the structure of formula 3b, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X is either O (oxygen) or S (sulfur);

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z_(b) is N or C, Z₇ is N or C, wherein no more than two of Z₁,Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR, are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl), thioalkoxy(—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio; and

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),—(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, the carbon-carbon double bond of thefive-membered nitrogen-containing ring can be saturated. The compoundsdescribed herein include stereoisomers or diastereomers of the saturatedcarbon atoms. The saturation can be hydrogen or C₁-C₆ alkyl groups addedto the carbon-carbon bond. In certain embodiments, Z₁ is CR₄, Z₂ is CR₅,Z₃ is CR₆, Z₄ is CR₇, Z₅ is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo,cyano, formyl, or nitro and each of R₅, R₆, R₇, and R₈ is H. In certainembodiments, R_(2a) is substituted amino. Substituted amino can includealkyl amino, for example, unsubstituted alkylamino, hydroxyalkylamino oralkoxyalkylamino, or cycloalkyl amino, for example, —NR_(a)R_(b) whereR_(a) and R_(b) together form a 3, 4, 5, 6, 7, or 8 member alkylenering. The alkylene ring can be unsubstituted or substituted, forexample, with halo, hydroxyl, alkoxy, or alkyl (including substitutedalkyl) groups. In certain embodiments, at least one of R₄, R₅, R₆, andR₇ is halo, e.g., F, Cl or Br.

In some embodiments, the compound has the structure of formula 4, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X is O (oxygen) or S (sulfur);

Y is a bond, O (oxygen), S (sulfur), or

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from thegroup consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is directlyconnected to S), wherein R₁₀ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl;

R₂ and R₃ are together selected from the group consisting of ═O, ═S, or═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H, C₁-C₆alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, the carbon-carbon double bond of thefive-membered nitrogen-containing ring can be saturated. The compoundsdescribed herein include stereoisomers or diastereomers of the saturatedcarbon atoms. The saturation can be hydrogen or C₁-C₆ alkyl groups addedto the carbon-carbon bond. In certain embodiments, Z₁ is CR₄, Z₂ is CR₅,Z₃ is CR₆, Z₄ is CR₇, Z₅ is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo,cyano, formyl, or nitro and each of R₅, R₆, R₇, and R₈ is H. In certainembodiments, at least one of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl orBr.

In some embodiments, the compound has the structure of formula 5, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

X is O (oxygen) or S (sulfur);

Y is a bond, O (oxygen), S (sulfur), or

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₂ and R₉ are each independently selected from the group consisting ofhydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,—NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a),—(C₀-C₆ CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a), —(C₀-C₆alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, the carbon-carbon double bond of thefive-membered nitrogen-containing ring can be saturated. The compoundsdescribed herein include stereoisomers or diastereomers of the saturatedcarbon atoms. The saturation can be hydrogen or C1-C6 alkyl groups addedto the carbon-carbon bond. In certain embodiments, Z₁ is CR₄, Z₂ is CR₅,Z₃ is CR₆, Z₄ is CR₇, Z₅ is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo,cyano, formyl, or nitro and each of R₅, R₆, R₇, and R₈ is H. In certainembodiments, at least one of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl orBr. In certain embodiments, R_(2a) is substituted amino. Substitutedamino can include alkyl amino, for example, unsubstituted alkylamino,hydroxyalkylamino or alkoxyalkylamino, or cycloalkyl amino, for example,—NR_(a)R_(b) where R_(a) and R_(b) together form a 3, 4, 5, 6, 7, or 8member alkylene ring. The alkylene ring can be unsubstituted orsubstituted, for example, with halo, hydroxyl, alkoxy, or alkyl(including substituted alkyl) groups.

In still another embodiment, the compound has structural formula 6, oran enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein:

R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b) is H,C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆ acyloxy, amino, orC₁-C₆ acyl, or

R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein R_(b) andR_(c) are each independently H, C₁-C₆ alkyl, alkoxy (—O-alkyl),thioalkoxy (—S-alkyl), cyano (—CN), or amino, or

R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, whereinR_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or

R₁ and R_(1a) are each independently selected from the group consistingof hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₄ (n=0 to 2, R₁₄ is directly connected to S), wherein R₁₄ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, andhalothiocarbonylthio;

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl;

B₁, B₂, B₃, B₄, B₅, and B₆ are each independently C or N;

R₉ and R₁₀, the number of which, together, complete the valence of eachof B₁, B₂, B₃, B₄, B₅, and B₆, are each independently selected from thegroup consisting of hydrogen, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b),—(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b),—(C₀-C₆ alkyl)-SO₂NHCOR_(2a), —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and—S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein R₁₂ isselected from the group consisting of hydrogen, deuterium, halo, amino,hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and

wherein R_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

wherein R₂ and R₃ are together selected from the group consisting of ═O,═S, or ═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H,C₁-C₆ alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₃ (n=0 to 2, R₁₃ is directlyconnected to S), wherein R₁₃ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, Z₁ is CR₄, Z₂ is CR₅, Z₃ is CR₆, Z₄ is CR₇, Z₅is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo, cyano, formyl, or nitroand each of R₅, R₆, R₇, and R₈ is H. In certain embodiments, at leastone of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl or Br. In certainembodiments, R_(2a) is substituted amino. Substituted amino can includealkyl amino, for example, unsubstituted alkylamino, hydroxyalkylamino oralkoxyalkylamino, or cycloalkyl amino, for example, —NR_(a)R_(b) whereR_(a) and R_(b) together form a 3, 4, 5, 6, 7, or 8 member alkylenering. The alkylene ring can be unsubstituted or substituted, forexample, with halo, hydroxyl, alkoxy, or alkyl (including substitutedalkyl) groups.

In some embodiments, the compound has structural formula 7, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

Y is a bond, O (oxygen), S (sulfur), or

Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇, Z₅ is Nor CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two of Z₁, Z₂,Z₃, Z₄, Z₅, Z₆, and Z₇ are N;

R₄, R₅, R₆, R₇, and R₈ are each independently selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directlyconnected to S), wherein R₁₁ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio;

R_(N) is H, CN, C₁-C₆ alkyl, —OH, —(CO)—OR, or —OR, wherein R is H,C₁-C₆ alkyl, or C₁-C₆ acyl;

B₁, B₂, B₃, B₄, B₅, and B₆ are each independently C or N;

R₉ and R₁₀, the number of which, together, complete the valence of eachof B₁, B₂, B₃, B₄, B₅, and B₆, are each independently selected from thegroup consisting of hydrogen, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b),—(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b),—(C₀-C₆ alkyl)-SO₂NHCOR_(2a), —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₂ (n=0 to 2, R₁₂is directly connected to S), wherein R₁₂ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and

wherein R_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;

wherein R₂ and R₃ are together selected from the group consisting of ═O,═S, or ═NR_(a) (R_(a) is H, C₁-C₆ alkyl, C₁-C₆ acyl, or —OR, R is H,C₁-C₆ alkyl, or C₁-C₆ acyl), or

R₂ and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₃ (n=0 to 2, R₁₃ is directlyconnected to S), wherein R₁₃ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio; and

optionally, adjacent R groups, together, can form a six- totwelve-membered ring.

In certain embodiments, Z₁ is CR₄, Z₂ is CR₅, Z₃ is CR₆, Z₄ is CR₇, Z₅is CR₈, Z₆ is C, Z₇ is C, wherein R₄ is halo, cyano, formyl, or nitroand each of R₅, R₆, R₇, and R₈ is H. In certain embodiments, at leastone of R₄, R₅, R₆, and R₇ is halo, e.g., F, Cl or Br. In certainembodiments, R_(2a) is substituted amino. Substituted amino can includealkyl amino, for example, unsubstituted alkylamino, hydroxyalkylamino oralkoxyalkylamino, or cycloalkyl amino, for example, —NR_(a)R_(b) whereR_(a) and R_(b) together form a 3, 4, 5, 6, 7, or 8 member alkylenering. The alkylene ring can be unsubstituted or substituted, forexample, with halo, hydroxyl, alkoxy, or alkyl (including substitutedalkyl) groups.

In each of the formulae, in some embodiments, each of R₄, R₅, R₆, and R₇is hydrogen. In other embodiments, at least one of R₄, R₅, R₆, and R₇can be F, Cl or Br and the others of R₄, R₅, R₆, and R₇ are hydrogen. Instill other embodiments, at least two of R₄, R₅, R₆, and R₇,independently, can be F, Cl or Br and the others of R₄, R₅, R₆, and R₇are hydrogen. The F, Cl or Br can be at the indole ring carbon 5, 6, or7.

In each of formulae 3, 3a, 3b, 3c, and 5, in certain embodiments, R₉ canbe hydrogen. R₂ can be acyl, cyano, hydroxyl-substituted C1-C6 alkyl,amino-substituted C1-C6 alkyl, aryl, or heteroaryl. The aryl orheteroaryl can be substituted or unsubstituted. The substituted aryl orheteroaryl can be substituted with halo, amino, hydroxyl, or C1-C6alkyl. The amino can be unsubstituted.

In each of formulae 2, 2a, and 4, in certain embodiments, R₂ can behydroxyl or amino and R₃ can be alkyl, aryl, nitro, or cyano. R₉ can behydrogen. The amino can be substituted or unsubstituted.

In some embodiments, the compound has structural formula 8, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof:

wherein R₂ is selected from the group consisting of substituted alkyl,heteroaryl, and

wherein R_(2a) is H, C1-C6 alkyl, alkoxy (—O-alkyl), hydroxy, thioalkoxy(—S-alkyl), cyano (—CN), or amino; and

R₄, R₅, R₆, and R₇, are each independently selected from the groupconsisting of hydrogen and halo.

In some embodiments, R₂ is substituted alkyl, e.g., a C1-C6 alkylsubstituted with one or more hydroxyl, amino, nitro, or cyano. In someembodiments, R₂ is heteroaryl, e.g., oxadiazolyl or thiadiazolyl,optionally substituted with one or more hydroxyl, amino, nitro, cyano,C1-C6 alkyl, or C1-C6 alkyl amino. In some embodiments, R₂ is—C(O)—R_(2a), and R_(2a) is C1-C6 alkyl.

In one embodiment of the compound of structural formula 8, at least oneof R₄, R₅, R₆, and R₇ is F, Cl or Br and the others of R₄, R₅, R₆, andR₇ are hydrogen. In another embodiment, at least two of R₄, R₅, R₆, andR₇ are F, Cl or Br and the others of R₄, R₅, R₆, and R₇ are hydrogen.

In one embodiment, R₅ is F and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is F and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is F and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ is Cl and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is Cl and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is Cl and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ and R₆ are F and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are F and R₄ and R₆ are hydrogen. In stillanother embodiment, R₆ and R₇ are F and R₄ and R₅ are hydrogen.

In one embodiment, R₅ and R₆ are Cl and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are Cl and R₄ and R₆ are hydrogen. Instill another embodiment, R₆ and R₇ are Cl and R₄ and R₅ are hydrogen.

In some embodiments, each of R₄, R₅, R₆ and R₇ is hydrogen.

Exemplary compounds of the present disclosure are shown in Table 1.

TABLE 1 Representative Indole Compounds ARI-# Structural Formula ¹H NMRData Mass Characterization 001

002

003

004

005

006

007

¹H NMR (500 MHz, DMSO-d₆) δ 12.81 (s, 1H), 9.12 (s, 1H), 8.89-8.64 (m,1H), 8.77 (s, 1H), 7.62- 7.59 (m, 1H), 7.38- 7.35 (m, 2H), 3.90 (s, 3H).ESI MS m/z 303 [M + H]⁺ 008

¹H NMR (500 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.99 (d, J = 3.5 Hz, 1H),8.30-8.28 (m, 2H), 7.60-7.57 (m, 1H), 7.32-7.28 (m, 2H). ESI MS m/z 302[M + H]⁺ 009

¹H NMR (500 MHz, DMSO-d₆) δ 12.81 (s, 1H), 10.77 (s, 1H), 9.15 (s, 1H),8.31 (dd, J = 6.5, 2.0 Hz, 1H), 7.60 (s, 1H), 7.55 (dd, J = 6.0, 1.5 Hz,1H), 7.30-7.55 (m, 2H), 3.73 (s, 3H). ESI MS m/z 302 [M + H]⁺ 011

¹H NMR (500 MHz, CDCl₃, 1.4:1 mixture of oxime (E), (Z)- isomers) δ 8.77(s, 1H), 8.51 (d, J = 3.0 0.7H), 8.45 (s, 0.7H), 8.39 (s, 0.7H), 8.35-8.34 (m, 0.7H), 8.21 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.47-7.38 (m,1.7H), 7.32-7.30 (m, 1H), 7.24-7.20 (m, 1.4H), 7.17-7.14 ESI MS m/z 316[M + H]⁺ (m, 1H), 7.11-7.08 (m, 1H), 4.29 (s, 2.1H), 4.13 (s, 3H), 3.97(s, 2.1H), 3.89 (s, 3H). 013

¹H NMR (500 MHz, DMSO-d₆) δ 12.43 (s, 1H), 9.12 (d, J = 3.0 Hz, 1H),8.86 (s, 1H), 8.33-8.31 (m, 1H), 7.61-7.59 (m, 1H), 7.33-7.30 (m, 2H),2.48 (s, 3H). ESI MS m/z 303 [M + H]⁺ 014

¹H NMR (500 MHz DMSO-d₆, 3.8:1 mixture of oxime (E), (Z)-isomers) δ12.81 (s, 1 H), 12.06 (s, 0.26H), 11.68 (s, 0.26H), 11.47 (s, 1H), 8.77(s, 1H), 8.56 (s, 0.26 H), 8.40 (d, J = 3.0 Hz, 1H), 8.14 (d, J = 8.0Hz, 1H), 7.87 (d, J = 2.5 Hz, 0.26H), 7.46-7.44 (m, 1.26 H), 7.29 (d, JESI MS m/z 302 [M + H]⁺ J = 8.0 Hz, 0.26H), 7.18-7.08 (m, 2.26H), 7.00(t, J = 8.0 Hz, 0.26H), 3.89 (s, 3H), 3.80 (s, 0.82H). 015

¹H NMR (500 MHz, CDCl₃) δ 9.07 (s, 1H), 8.53-8.51 (m, 1H), 8.40 (s, 1H),7.42- 7.36 (m, 3H), 3.04 (s, 3H), 3.94 (s, 3H). ESI MS m/z 301 [M + H]⁺016

¹H NMR (500 MHz, CDCl₃) δ 8.76 (d, , J = 3.0 Hz, 1H), 8.70 (s, 1H),8.44-8.43 (m, 1H), 7.43-7.42 (m, 1H), 7.34-7.32 (m, 2H), 5.0 (s, 1H),3.85 (s, 3H), 1.79 (s, 3H), 1.4 (s, 3H). ESI MS m/z 317 [M + H]⁺ 017

¹H NMR (500 MHz, CDCl₃, 2.3:1 mixture of (E), (Z)-isomers) δ 8.32, 8.29(s, 1.26 H), 8.16 (s, 1H), 7.94 (s, 0.4 H), 7.85 (s, 0.4 H), 7.60-7.57(m, 2H), 7.43-7.36 (m, 2.5H), 7.24-7.17 (m, 1.7H), 7.12-7.08 (m, 1.48H),6.98 (s, 1 H), 4.02 (s, 3H), 1.29 (s, 1.29 H), 3.88 (s, 4.28 H). ESI MSm/z 315 [M + H]⁺ 018

¹H NMR (500 MHz, CDCl₃, 1.8:1 mixture of (E), (Z)-isomers) δ 8.34 (bs,0.89 H), 8.17-7.16 (m, 1H), 8.01 (s, 0.94 H), 7.50- 7.44 (m, 1.86 H),7.40-7.28 (m, 4.10 H), 7.25-7.17 (m, 2.37H), 7.13-7.08 (m, 1.61H), 6.40(q, J = 7.0 Hz, 0.52H), 3.97 (s, 1.67H), 3.96 (s, 3H), 2.19 (d, ESI MSm/z 299 [M + H]⁺ J = 7.0 Hz, 1.68 H), 1.80 (d, J = 7.0 Hz, 3.0H). 019

¹H NMR (500 MHz, CDCl₃, key protons reported) δ 8.30 (bs, 1H, indoleNH), 6.26 (d, J = 0.8 Hz, 1H, olefin), 5.83 (bs, 1H, olefin), 3.96 (s,3H, methyl ester). ESI MS m/z 285 [M + H]⁺ 020

¹H NMR (500 MHz, CDCl₃) δ 8.23 (s, 1H), 8.01 (s, 1H), 7.41- 7.39 (m,1H), 7.34- 7.32 (m, 1H), 7.22- 7.19 (m, 1H), 7.17 (d, J = 2.5 Hz, 1H),7.10- 7.07, (m, 1H), 3.95 (s, 3H), 2.37 (s, 3H), 1,83 (s, 3H). ESI MSm/z 313 [M + H]⁺ 021

¹H NMR (500 MHz, DMSO-d₆) δ 12.40 (s, 1H), 11.43 (s, 1H), 9.11 (s, 1H),8.32-8.30 (m, 1H), 7.91 (s, 1H) 7.57-7.55 (m, 1H), 7.31-7.26 (m, 2H),2.12 (s, 3H). ESI MS m/z 284 [M − H]⁻ 022

¹H NMR (500 MHz, DMSO-d₆) δ 12.38 (s, 1H), 9.10 (s, 1H), 8.87 (s, 1H),8.32-8.30 (m, 1H), 7.60-7.58 (m, 1H), 7.32-7.29 (m, 2H), 4.61 (t, , J =5.0 Hz, 1H), 4.40 (app t, J = 6.5 Hz, 2H), 3.58 (app q, J = 6.1, Hz,2H), 1.90 (quint, J = 6.4 Hz, 2H). ESI MS m/z 331 [M + H]⁺ 023

¹H NMR (500 MHz, DMSO-d₆) δ 12.30 (s, 1H), 9.11 (s, 1H), 8.89 (s, 1H),8.32-8.30 (m, 1H), 7.60-7.58 (m, 1H), 7.32-7.28 (m, 2H), 4.96 (t, , J =5.0 Hz, 1H), 4.36 (app t, J = 6.0 Hz, 2H), 3.73 (app q, J = 5.5, Hz,2H). ESI MS m/z 317 [M + H]⁺ 024

¹H NMR (500 MHz, DMSO-d₆) δ 11.20 (s, 1H), 8.51 (s, 1H), 7.45 (d, , J =2.5 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 (d, , J = 8.0 Hz, 1H),7.09-7.06 (m, 1H), 6.95-6.92 (m, 1H), 5.89 (s, 1H), 3.76 (s, 3H), 3.34(s, 3H). ESI MS m/z 303 [M + H]⁺ ESI MS m/z 271 [M + H − CH₃OH]⁺ 025

¹H NMR (500 MHz, CDCl₃) δ 9.35 (d, J = 1.5 Hz, 1H), 9.11 (s, 1H), 8.52(d, J = 2 Hz, 1H), 8.45 (s, 1H), 7.46 (dd, J = 7, 1.5 Hz, 1H), 7.37-7.31(m, 2H), 4.58-4.57 (m, 2H), 3.91-3.89 (m, 2H), 3.85 (app dd, J = 4.0,2.0 Hz, 2H), 3.74 (app dd, J = 6.0, 3.0 Hz, 2H). ESI MS m/z 361 [M + H]⁺026

¹H NMR (500 MHz, DMSO-d₆) δ 12.39 (s, 1H), 9.18 (s, 1H), 9.03 (d, J = 3Hz, 1H), 8.29-8.28 (m, 1H), 7.60-7.58 (m, 1H), 7.33-7.27 (m, 2H). ESI MSm/z 254 [M + H]⁺ 028

¹H NMR (500 MHz, CDCl₃) δ 9.17 (1, , J = 3.0 Hz, 1H), 8.74 (s, 1H), 8.53(dd, J = 8.5, 1.5 Hz, 1H), 7.73 (s, 1H), 7.46-7.44 (m, 1H), 7.37-7.30(m, 2H), 6.11 (s, 1H), 4.20-4.10 (m, 4H). ESI MS m/z 301 [M + H]⁺ 029

¹H NMR (500 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.04 (s, 1H), 8.32-8.30 (m,1H), 8.03 (s, 1H), 7.58- 7.57 (m, 1H), 7.31- 7.25 (m, 2H), 5.68 (d, J =1.0 Hz, 1H), 3.34 (s, 3H), 3.31 (s, 3H). ESI MS m/z 303 [M + H]⁺ 030

¹H NMR (500 MHz, DMSO-d₆) δ 12.35 (s, 1H), 9.14 (s, 1H), 8.78 (s, 1H),8.34-8.31 (m, 1H), 7.61-7.59 (m, 1H), 7.33-7.28 (m, 2H), 2.72 (s, 3H).ESI MS m/z 309 [M − H]⁻ 031

¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 9.14 (s, 1H), 9.10 (s, 1H),8.33-8.31 (m, 1H), 7.62-7.60 (m, 1H), 7.33-7.29 (m, 2H), 2.48 (s, 3H).ESI MS m/z 309 [M − H]⁻ 032

¹H NMR (500 MHz, DMSO-d₆) δ 12.20 (s, 1H), 9.11 (s, 1H), 8.43-8.39 (m,1H), 8.30-8.22 (m, 3H), 7.56-7.52 (m, 1H), 7.29-7.26 (m, 2H), 3.98 (s,3H). ESI MS m/z 279 [M − H]⁻ 033

¹H NMR (500 MHz, DMSO-d₆) δ 12.35 (s, 1H), 9.43 (d, J = 3.0 Hz, 1H),8.79 (t, J = 5.5 Hz, 1H), 8.59 (s, 1H), 8.35-8.31 (m, 1H), 7.59-7.55 (m,1H), 7.32-7.26 (m, 2H), 3.41-3.36 (m, 2H), 1.19 (t, J = 7.0 Hz, 3H). ESIMS m/z 300 [M + H]⁺ 034

¹H NMR (500 MHz, DMSO-d₆) δ 12.42 (s, 1H), 9.38 (s, 1H), 8.59 (s, 1H),8.42 (d, J = 3.0 Hz, 1H), 8.34-8.30 (m, 1H), 7.57-7.54 (m, 1H),7.31-7.26 (m, 2H), 4.21-4.14 (m, 1H), 1.26 (s, 3H), 1.25 (s, 3H). ESI MSm/z 314 [M + H]⁺ 035

¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 9.41 (s, 1H), 8.73 (t, J =6.0 Hz, 1H), 8.59 (s, 1H), 8.33-8.31 (m, 1H), 7.57-7.56 (m, 1H),7.32-7.28 (m, 2H), 3.18 (t, J = 6.5 Hz, 2H), 1.96-1.90 (m, 1H), 0.93 (s,3H), 0.92 (s, 3H). ESI MS m/z 328 [M + H]⁺ 036

¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 9.40 (s, 1H), 8.69 (t, J =5.5 Hz, 1H), 8.61 (s, 1H), 8.33-8.31 (m, 1H), 7.58-7.56 (m, 1H),7.32-7.26 (m, 2H), 4.81 (t, J = 5.5 Hz, 1H), 3.58 (dd, J = 12.0, 6.5 Hz,2H), 3.43 (dd, J = 12.0, 6.0 Hz, 2H). ESI MS m/z 316 [M + H]⁺ 037

¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 9.40 (s, 1H), 8.76 (bs, 1H),8.61 (s, 1H), 8.33-8.31 (m, 1H), 7.58-7.55 (m, 1H), 7.32-7.26 (m, 2H),3.52-3.51 (m, 4H), 3.30 (s, 3H). ESI MS m/z 330 [M + H]⁺ 038

¹H NMR (500 MHz, DMSO-d₆) δ 9.32 (s, 1H), 9.01 (s, 1H), 8.38 (d, J = 7.0Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.63-7.55 (m, 2H), 3.94 (s, 3H). ESIMS m/z 312 [M + H]⁺ 039

¹H NMR (500 MHz, DMSO-d₆) δ 12.44 (s, 1H), 9.28 (d, J = 3.0 Hz, 1H),8.57 (s, 1H), 8.32-8.29 (m, 1H), 7.81 (bs, 1H), 7.57- 7.53 (m, 1H),7.31- 7.26 (m, 2H), 1.46 (s, 9H). ESI MS m/z 328 [M + H]⁺ 040

¹H NMR (500 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.97 (s, 1H), 8.32-8.30 (m,1H), 8.07 (s, 1H), 7.58- 7.56 (m, 1H), 7.31- 7.27 (m, 2H), 2.88 (s, 4H).ESI MS m/z 324 [M − H]⁻ 041

¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 9.10 (s, 1H), 8.87 (s, 1H),8.30-8.35 (m, 1H), 7.55-7.62 (m, 1H), 7.28-7.33 (m, 2H), 4.39 (q, J =7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). ESI MS m/z 301 [M + H]⁺ 042

¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 9.10 (s, 1H), 8.83 (s, 1H),8.30-8.33 (m, 1H), 7.57-7.61 (m, 1H), 7.26-7.34 (m, 2H), 5.15-5.24 (m,1H), 1.23 (s, 6H). ESI MS m/z 315 [M + H]⁺ 043

¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.11 (s, 1H), 8.89 (s, 1H),8.30-8.33 (m, 1H), 7.57-7.62 (m, 1H), 7.28-7.35 (m, 2H), 4.30 (t, J =6.4 Hz, 2H), 1.72-1.80 (m, 2H), 1.0 (t, J = 7.2 Hz, 3H). ESI MS m/z 315[M + H]⁺ 044

¹H NMR (500 MHz, DMSO-d₆) δ 12.30 (s, 1H), 9.00 (d, J = 3.5 Hz, 1H),8.65 (s, 1H), 8.31-8.29 (m, 1H), 7.58-7.55 (m, 1H), 7.32-7.26 (m, 2H),4.73 (d, J = 7.5 Hz, 2H), 4.12 (d, J = 7.5 Hz, 2H), 2.38-2.31 (m, 2H).ESI MS m/z 312 [M + H]⁺ 045

¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 8.99 (d, J = 3.5 Hz, 1H),8.66 (s, 1H), 8.31-8.29 (m, 1H), 7.58-7.56 (m, 1H), 7.32-7.30 (m, 2H),5.82 (d, J = 7.0 Hz, 1H), 4.92-4.89 (m, 1H), 4.60-4.55 (m, 1H),4.43-4.40 (m, 1H), 4.34-4.31 (m, 1H), 3.85 (dd, J = 10.5, ESI MS m/z 328[M + H]⁺ 3.5 Hz, 1H). 046

¹H NMR (500 MHz, DMSO-d₆) δ 12.34 (s, 1H), 9.00 (d, J = 3.0 Hz, 1H),8.68 (s, 1H), 8.31-8.28 (m, 1H), 7.59-7.56 (m, 1H), 7.32-7.28 (m, 2H),4.90-4.87 (m, 1H), 4.51 (dd, J = 10.0, 2.5 Hz, 1H), 4.34-4.28 (m, 2H),3.94-3.90 (m, 1H), 3.28 (s, 3H). ESI MS m/z 342 [M + H]⁺ 047

¹H NMR (500 MHz, DMSO-d₆) δ 12.14 (s, 1H), 8.63 (q, J = 4.5 Hz, 1H),8.57 (d, J = 3.0 Hz, 1H), 8.38- 8.35 (m, 1H), 8.22- 8.17 (m, 2H), 8.11(dd, J = 7.0, 2.5 Hz, 1H), 7.55-7.52 (m, 1H), 7.29-7.25 (m, 2H), 2.87(d, J = 4.5 Hz, 3H). ESI MS m/z 280 [M + H]⁺ 048

¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (bs, 1H), 9.12 (s, 1H), 8.88 (s, 1H),8.30-8.35 (m, 1H), 7.57-7.62 (m, 1H), 7.27-7.35 (m, 2H), 3.80-3.88 (m,1H), 1.22 (d, J = 6.8 Hz, 6H). ESI MS m/z 299 [M + H]⁺ 049

¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (bs, 1H), 9.50 (s, 1H), 8.74 (bs, 1H),8.62 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H),7.30-7.35 (m, 2H), 2.87 (d, J = 4.8 Hz, 3H). ESI MS m/z 318 [M − H]⁻ 050

¹H NMR (500 MHz, DMSO-d₆) δ 14.42 (s, 1H), 13.88 (s, 1H), 9.47-9.18 (m,1H), 8.51 (bs, 1H), 8.36 (dd, J = 7.0, 1.0 Hz, 1H), 7.67 (d, J = 7.5 Hz,1H), 7.38-7.34 (m, 2H), 4.02 (s, 3H), 2.41 (s, 2H). ESI MS m/z 324 [M +H]⁺ 052

¹H NMR (500 MHz, CDCl₃) δ 9.20 (d, J = 3.5 Hz, 1H), 8.71 (bs, 1H), 8.53(dd, J = 7.0, 2.0 Hz, 1H), 7.79 (s, 1H), 7.48-7.46 (m, 1H), 7.38-7.32(m, 2H), 3.27 (s, 1H). ESI MS m/z 253 [M + H]⁺ 053

¹H NMR (500 MHz, DMSO-d₆) δ 14.37 (s, 1H), 8.95 (s, 1H), 8.30 (d, J =8.5 Hz, 1H), 7.78 (d, J = 8.5, Hz, 1H), 7.55 (dt, J = 6.0, 1.0 Hz, 1H),7.43 (dt, J = 8.0, 0.5 Hz, 1H), 3.91 (s, 3H). ESI MS m/z 288 [M + H]⁺054

¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (bs, 1H), 9.07 (s, 1H), 8.31-8.34 (m,2H), 7.56-7.59 (m, 1H), 7.27-7.31 (m, 1H), 3.97 (s, 3H), 2.90 (q, J =7.6 Hz, 2H), 1.14- 1.25 (m, 3H). ESI MS m/z 314 [M + H]⁺ 055

¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H),8.28 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.32- 7.36 (m, 1H),3.94 (s, 3H). ESI MS m/z 319 [M − H]⁻ 056

¹H NMR (500 MHz, DMSO-d₆) δ 12.39 (s, 1H), 9.45 (s, 1H), 9.14 (d, J =3.5 Hz, 1H), 8.96 (s, 1H), 8.33- 8.32 (m, 1H), 7.62- 7.59 (m, 1H), 7.34-7.28 (m, 2H). ESI MS m/z 297 [M + H]⁺ 057

¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (bs, 1H), 9.49 (d, J = 3.2 Hz, 1H),8.70-8.74 (m, 1H), 8.62-8.85 (m, 2H), 7.95 (s, 1H), 2.87-2.89 (s, 3H).ESI MS m/z 440 [M − H]⁻ 058

¹H NMR (400 MHz, DMSO-d₆) δ 13.46 (bs, 1H), 12.76 (s, 1H), 9.17 (s, 1H),8.83 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H),7.31-7.35 (m, 1H). ESI MS m/z 305 [M − H]⁻ 059

¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (bs, 1H), 9.12 (s, 1H), 8.76 (s, 1H),8.30-8.33 (m, 1H), 7.58-7.61 (m, 1H), 7.28-7.33 (m, 2H), 1.60 (s, 9H).ESI MS m/z 329 [M + H]⁺ 060

¹H NMR (500 MHz, DMSO-d₆) 12.38 (s, 1H), 9.12 (d, J = 3.0 Hz, 1H), 8.87(s, 1H), 8.34-8.31 (m, 1H), 7.62-7.59 (m, 1H), 7.33-7.28 (m, 2H), 2.64(s, 3H). ESI MS m/z 311 [M + H]⁺ 061

¹H NMR (500 MHz, DMSO-d₆) δ 12.39 (s, 1H), 10.08 (s, 1H), 9.15 (s, 1H),9.03 (s, 1H), 8.32-8.30 (m, 1H), 7.60-7.58 (m, 1H), 7.33-7.28 (m, 2H).ESI MS m/z 257 [M + H]⁺ 062

¹H NMR (500 MHz, DMSO-d₆) δ 15.51, 15.19 (bs, 1H), 12.27 (s, 1H), 9.29(s, 1H), 8.70, 8.40 (bs, 2H), 8.36-8.32 (m, 1H), 7.60-7.57 (m, 1H),7.32-7.26 (m, 2H). ESI MS m/z 296 [M + H]⁺ 063

¹H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.31 (d, J = 2.5 Hz, 1H),8.34-8.30 (m, 1H), 8.20 (bs, 3H), 8.00 (d, J = 0.5 Hz, 1H), 7.57-7.53(m, 1H), 7.30-7.26 (m, 2H), 4.58 (s, 1H). ESI MS m/z 302 [M + H]⁺ 064

¹H NMR (500 MHz, DMSO-d₆) δ 14.46, 13.82 (bs, 1H), 12.40, 12.30 (bs,1H), 8.57, 8.41 (bs, 1H), 8.33 (br d, J = 8.5 Hz, 1H), 7.59 (br d, J =6.5 Hz, 1H), 7.32-7.28 (m, 2H), 2.45, 2.36 (s, 3H). ESI MS m/z 310 [M +H]⁺ 065

¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (bs, 1H), 9.50 (s, 1H), 8.74 (bs, 1H),8.62 (s, 1H), 7.98-7.99 (m, 1H), 7.58-7.62 (m, 1H), 7.14-7.20 (m, 1H),2.89 (d, J = 4.8 Hz, 3H). ESI MS m/z 304 [M + H]⁺ 066

¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.13 (s, 1H), 8.92 (s, 1H),7.96-8.00 (m, 1H), 7.61-7.65 (m, 1H), 7.17-7.21 (m, 1H), 3.95 (s, 3H).ESI MS m/z 303 [M − H]⁻ 067

¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (bs, 1H), 9.19 (s, 1H), 8.86 (s, 1H),8.29 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.31- 7.36 (m, 1H),3.25 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). ESI MS m/z 317 [M −H]⁻ 068

¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (bs, 1H), 9.15 (d, J = 2.0 Hz, 1H),8.30-8.34 (m, 1H), 7.82 (s, 1H), 7.55-7.60 (m, 1H), 7.26-7.30 (m, 2H),5.47 (d, J = 5.2 Hz, 1H), 4.71-4.77 (m, 1H), 1.90-2.00 (m, 1H),1.75-1.88 (m, 1H), 0.94 (t, J = 5.4 Hz, 3H). ESI MS m/z 287 [M + H]⁺ 069

¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (bs, 1H), 9.02 (s, 1H), 8.74 (s, 1H),8.31-8.33 (m, 1H), 7.56-7.59 (m, 1H), 7.28-7.31 (m, 2H), 3.95 (s, 3H),3.50-3.55 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H). ESI MS m/z 326 [M − H]⁻ 070

¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (bs, 1H), 9.09 (s, 1H), 8.30-8.34 (m,1H), 8.21 (s, 1H), 7.55- 7.60 (m, 1H), 7.26- 7.30 (m, 2H), 3.95 (s, 3H),3.65-3.69 (m, 1H), 1.24-1.32 (m, 6H). ESI MS m/z 328 [M + H]⁺ (This isthe syn or anti isomer of 069) 071

¹H NMR (500 MHz, DMSO-d₆) δ 12.37 (s, 1H), 9.82 (s, 1H), 9.15 (d, J =3.0 Hz, 1H), 8.85 (s, 1H), 8.35- 8.31 (m, 1H), 7.62- 7.59 (m, 1H), 7.33-7.28 (m, 2H). ESI MS m/z 297 [M + H]⁺ 072

¹H NMR (500 MHz, DMSO-d₆) δ 12.07 (s, 1H), 9.28 (d, J = 2.0 Hz, 1H),8.94 (d, J = 3.0 Hz, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.38- 8.36 (m, 1H),7.54- 7.52 (m, 1H), 7.27- 7.22 (m, 2H). ESI MS m/z 229 [M + H]⁺ 073

¹H NMR (500 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.26-8.24 (m, 1H), 7.93 (s,1H), 7.79-7.77 (m, 2H), 7.62-7.59 (m, 1H), 7.55-7.51 (m, 3H), 7.28-7.22(m, 2H). ESI MS m/z 222 [M + H]⁺ 074

¹H NMR (500 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.24 (dd, J = 6.5, 1.5 Hz,1H), 7.92 (d, J = 3.0 Hz, 1H), 7.58- 7.56 (m, 2H), 7.52- 7.50 (m, 1H),7.42- 7.41 (m, 2H), 7.27- 7.21 (m, 2H), 2.41 (s, 3H). ESI MS m/z 236[M + H]⁺ 075

¹H NMR (500 MHz, DMSO-d₆) δ 12.34 (s, 1H), 9.16 (s, 1H), 8.37-8.30 (m,1H), 7.92 (d, J = 1.0 Hz, 1H), 7.58-7.55 (m, 1H), 7.31-7.27 (m, 2H),5.35 (t, J = 8.0 Hz, 1H), 3.04 (d, J = 8.0 Hz, 2H). ESI MS m/z 283 [M +H]⁺ 076

¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 1H), 9.00 (s, 1H), 8.22 (d, J =1.2 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.50-7.53 (m, 1H), 7.37-7.40 (m,1H), 7.13-7.16 (m, 1H), 3.95 (s, 3H). ESI MS m/z 287 [M + H]⁺ 077

¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (bs, 1H), 9.18 (s, 1H), 8.86 (s, 1H),8.31-8.34 (m, 1H), 7.58-7.61 (m, 1H), 7.27-7.34 (m, 2H), 2.74 (s, 3H).ESI MS m/z 270.4 [M + H]⁺ 078

¹H NMR (400 MHz, DMSO-d6) δ 12.25 (bs, 1H), 9.39 (s, 1H), 8.71-8.73 (m,1H), 8.58 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H),6.91- 6.95 (m, 1H), 3.83 (s, 3H), 2.89 (d, J = 4.8 Hz, 3H). ESI MS m/z316 [M + H]⁺ 079

¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (bs, 1H), 8.72-8.80 (m, 1H), 8.72 (s,1H), 8.47 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H),7.35- 7.40 (m, 1H), 7.13- 7.18 (m, 1H), 2.92 (d, J = 4.8 Hz, 3H). ESI MSm/z 286 [M + H]⁺ 080

¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (bs, 1H), 9.03 1H), 8.88 (s, 1H), 7.83(d, J = 2.4 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 6.91-6.95 (m, 1H), 3.92(s, 3H), 3.83 (s, 3H). ESI MS m/z 317 [M + H^(]+) 081

¹H NMR (500 MHz, DMSO-d₆) δ 12.08 (s, 1H), 8.81 (d, J = 3.0 Hz, 1H),8.76-8.75 (m, 1H), 8.39-8.37 (m, 1H), 8.04-8.02 (m, 2H), 7.64-7.11 (m,1H), 7.54-7.51 (m, 1H), 7.27-7.23 (m, 2H). ESI MS m/z 223 [M + H]⁺ 082

¹H NMR (500 MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.29 (t, J = 1.5 Hz, 1H),8.24 (dd, J = 8.5, 1.5 Hz, 1H), 8.17 (dt, J = 8.0, 1.5 Hz, 1H), 8.06(dt, J = 8.0, 1.5 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 7.70 (t, J = 8.0Hz, 1H), 7.54-7.53 (m, 1H), 7.30-7.24 (m, 2H), 3.89 (s, 3H). ESI MS m/z280 [M + H]⁺ 083

¹H NMR (500 MHz, DMSO-d₆) δ 12.39 (s, 1H), 9.08 (s, 1H), 8.54 (s, 1H),8.33-8.31 (m, 1H), 7.61-7.59 (m, 1H), 7.41 (bs, 2H), 7.33-7.28 (m, 2H).ESI MS m/z 312 [M + H]⁺ 085

¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (bs, 1H), 9.40-9.44 (m, 2H), 8.59 (s,1H), 8.32-8.35 (m, 1H), 7.56-7.60 (m, 1H), 7.29-7.32 (m, 2H). ESI MS m/z249 [M + H]⁺ 086

¹H NMR (400 MHz, DMSO-d₆) δ 12.34 (bs, 1H), 9.58 (d, J = 1.6 Hz, 1H),8.80 (s, 1H), 8.41 (s, 1H), 8.33- 8.35 (m, 1H), 7.55- 7.58 (m, 1H),7.28- 7.32 (m, 2H), 3.97 (s, 3H). ESI MS m/z 280 [M − H]⁻ 087

¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (bs, 1H), 9.20 (s, 1H), 8.86 (s, 1H),7.97-8.00 (m, 1H), 7.60-7.63 (m, 1H), 7.16-7.19 (m, 1H), 3.24 (q, J =7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). ESI MS m/z 303 [M + H]⁺ 088

¹H NMR (500 MHz, DMSO-d₆) δ 12.32 (s, 1H), 9.09 (s, 1H), 8.30-8.32 (m,1H), 8.18 (s, 1H), 7.57- 7.55 (m, 1H), 7.31- 7.25 (m, 2H), 7.15 (d, J =6.0 Hz, 1H), 5.50 (7, J = 7.0 Hz, 1H). ESI MS m/z 327 [M + H]⁺ 089

¹H NMR (500 MHz, CD₃OD, partial CD₃O- adduct) δ 9.25, 9.17 (s, 1H),8.39-8.36 (m, 1H), 8.12, 8.07 (s, 1H), 7.51-7.48 (m, 1H), 7.30-7.25 (m,2H). As hydrate, ESI MS m/z 343 [M + H + H₂O]⁺ 090

¹H NMR (500 MHz, DMSO-d₆) δ 12.38 (bs, 1H), 9.02 (d, J = 3.5 Hz, 1H),8.53 (s, 1H), 8.34-8.30 (m, 1H), 7.61-7.57 (m, 1H), 7.52 (bs, 2H), 7.33-7.27 (m, 2H). ESI MS m/z 328 [M + H]⁺ 091

¹H NMR (500 MHz, DMSO-d₆) δ 12.18 (s, 1H), 8.25 (dd, J = 5.0, 1.5 Hz,1H), 8.18- 8.17 (m, 1H), 8.09- 8.03 (m, 3H), 7.75 (dt, J = 8.0, 0.5 Hz,1H), 7.54-7.52 (m, 1H), 7.30-7.24 (m, 2H). ESI MS m/z 247 [M + H]⁺ 092

¹H NMR (400 MHz, DMSO-d₆) δ 12.21 (bs, 1H), 9.10 (s, 1H), 8.30-8.34 (m,1H), 7.82 (s, 1H), 7.55- 7.60 (m, 1H), 7.24- 7.31 (m, 2H), 5.45 (d, J =6.8 Hz, 1H), 4.70- 7.77 (m, 1H), 1.88- 1.95 (m, 1H), 1.75- 1.85 (m, 1H),0.93 (t, J = 6.0 Hz, 3H). ESI MS m/z 287 [M + H]⁺ 093

¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (bs, 1H), 9.37 (s, 1H), 9.31 (s, 1H),8.36 (s, 1H), 8.33-8.37 (m, 1H), 7.55-7.59 (m, 1H), 7.29-7.33 (m, 2H).ESI MS m/z 248.4 [M + H]⁺ 094

¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (bs, 1H), 9.10 (s, 1H), 8.30-8.34 (m,1H), 7.82 (s, 1H), 7.55- 7.60 (m, 1H), 7.24- 7.31 (m, 2H), 5.45 (d, J =6.0 Hz, 1H), 4.70- 4.77 (m, 1H), 1.88- 2.05 (m, 1H), 1.74- 1.85 (m, 1H),0.95 (t, J = 6.0 Hz, 3H). ESI MS m/z 287 [M + H]⁺ 095

¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (bs, 1H), 9.34 (d, J = 1.2 Hz, 1H),9.28 (d, J = 1.2 Hz, 1H), 8.68 (s, 1H), 8.35-8.38 (m, 1H), 7.55-7.58 (m,1H), 7.29-7.32 (m, 2H). ESI MS m/z 280 [M − H]⁻ 096

¹H NMR (500 MHz, DMSO-d₆) δ 12.49 (s, 1H), 9.16 (d, J = 1.5 Hz, 1H),9.11 (d, J = 2.0 Hz, 1H), 8.29 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H),7.35-7.33 (m, 1H), 2.48 (s, 3H). ESI MS m/z 343 [M − H]⁻ 097

¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (bs, 1H), 9.18 (s, 1H), 8.87 (s, 1H),8.61 (s, 1H), 8.01 (s, 1H), 3.23- 3.26 (m, 2H), 1.13- 1.16 (m, 3H). ESIMS m/z 440 [M + H]⁺ 099

¹H NMR (500 MHz, DMSO-d₆) δ 12.54 (s, 1H), 9.20 (s, 1H), 9.08 (d, J =3.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.34(dd, J = 9.0, 5.0 Hz, 1H). ESI MS m/z 286 [M − H]⁻ 100

¹H NMR (500 MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.13 (d, J = 3.0 Hz, 1H),8.32-8.30 (m, 1H), 8.15 (s, 1H), 7.57-7.55 (m, 1H), 7.31-7.55 (m, 2H),4.86-4.81 (m, 1H), 2.71 (d, J = 8.0 Hz, 2H). ESI MS m/z 326 [M + H]⁺ 101

¹H NMR (400 MHz, DMSO-d₆) δ 12.97 (bs, 1H), 9.11 (s, 1H), 8.92 (s, 1H),8.12 (d, J = 7.6 Hz, 1H), 7.26-7.30 (m, 1H), 7.15-7.25 (m, 1H), 3.96 (s,3H). ESI MS m/z 305 [M + H]⁺ 102

¹H NMR (400 MHz, DMSO-d₆) δ 13.47 (bs, 1H), 12.96 (s, 1H), 9.17 (s, 1H),8.83 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.27-7.30 (m, 1H), 7.17-7.20 (m,1H). ESI MS m/z 289 [M − H]⁻ 103

¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (bs, 1H), 8.74 (s, 1H), 8.72-8.74 (m,1H), 8.42 (d, J = 1.2 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.56 (d, J =8.0 Hz, 1H), 7.36- 7.40 (m, 1H), 2.92 (d, J = 4.8 Hz, 3H). ESI MS m/z320 [M + H]⁺ 104

¹H NMR (400 MHz, DMSO-d₆) δ 13.05 (bs, 1H), 9.21 (s, 1H), 9.02 (s, 1H),8.10 (d, J = 8.0 Hz, 1H), 7.26-7.33 (m, 1H), 7.16-7.20 (m, 1H). ESI MSm/z 270 [M − H]⁻ 105

¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (bs, 1H), 12.27 (s, 1H), 8.92 (s, 1H),8.23 (s, 1H), 7.65 (m, 1H), 7.51 (m, 1H), 7.25 (m, 1H). ESI MS m/z 289[M − H]⁻ 106

¹H NMR (400 MHz, DMSO-d₆) δ 13.56 (bs, 1H), 12.35 (s, 1H), 8.92 (s, 1H),8.20 (s, 1H), 7.97 (d, J = 4.5 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H),7.35-7.39 (m, 1H). ESI MS m/z 305 [M − H]⁻ 107

¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (bs, 1H), 9.30 (s, 1H), 8.14 (s, 1H),7.63-7.70 (m, 1H), 7.51-7.55 (m, 1H), 7.23- 7.30 (m, 1H) ESI MS m/z 270[M − H]⁻ 108

¹H NMR (400 MHz, DMSO-d₆) δ 12.21 (bs, 1H), 8.70-8.80 (m, 2H), 8.43 (s,1H), 7.50-8.60 (m, 2H), 7.26 (m, 1H), 2.92 (d, J = 4.8 Hz, 3H). ESI MSm/z 302 [M − H]⁻ 109

¹H NMR (500 MHz, DMSO-d₆ δ 12.50 (d, J = 2.0 Hz, 1H), 9.16 (d, J = 3.5Hz, 1H), 8.81 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.5 Hz,1H), 7.34 (dd, J = 8.5, 2.0 Hz, 1H), 2.72 (s, 3H). ESI MS m/z 343 [M −H]⁻ 110

¹H NMR (500 MHz, DMSO-d₆) δ 12.34 (s, 1H), 9.12 (s, 1H), 8.55 (s, 1H),8.33-8.32 (m, 1H), 8.06 (s, 2H), 7.60-7.59 (m, 1H), 7.32-7.27 (m, 2H).ESI MS m/z 312 [M + H]⁺ 111

¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (bs, 1H), 9.26 (s, 1H), 8.94 (s, 1H),8.41-8.44 (m, 1H), 8.15 (s, 1H), 7.65-7.69 (m, 1H), 3.93 (s, 3H). ESI MSm/z 310 [M − H]⁻ 112

¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (bs, 1H), 9.21 (s, 1H), 9.08 (s, 1H),7.93-7.98 (m, 1H), 7.60-7.65 (m, 1H), 7.15-7.22 (m, 1H) ESI MS m/z 270[M − H]⁻ 113

¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (bs, 1H), 9.30 (s, 1H), 8.12 (s, 1H),7.96 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H). ESI MSm/z 286 [M − H]⁻ 114

¹H NMR (400 MHz, DMSO-d₆) δ 12.98 (bs, 1H), 9.16 (s, 1H), 8.82 (s, 1H),8.14 (d, J = 8.0 Hz, 1H), 7.28-7.31 (m, 1H), 7.16-7.22 (m, 1H), 2.73 (s,3H). ESI MS m/z 327 [M − H]⁻ 116

¹H NMR (500 MHz, DMSO-d₆) δ 12.52 (s, 1H), 9.15 (s, 1H), 9.04 (s, 1H),8.30 (m, 1H), 7.65 (dd, J = 8.5, 0.5 Hz, 1H), 7.34 (dd, J = 9.0, 2.5 Hz,1H). ESI MS m/z 397 [M − H]⁻ 117

¹H NMR (500 MHz, DMSO-d₆) δ 12.35 (s, 1H), 9.12 (d, J = 3.0 Hz, 1H),8.59 (s, 1H), 8.46-8.44 (m, 1H), 8.33-8.31 (m, 1H), 7.60-7.58 (m, 1H),7.32-7.27 (m, 2H), 2.96 (d, J = 4.5 Hz, 3H). ESI MS m/z 326 [M + H]⁺ 118

¹H NMR (400 MHz, DMSO-d₆) δ 13.03 (bs, 1H), 9.10 (s, 1H), 8.58 (s, 1H),8.14 (d, J = 8.0 Hz, 1H), 7.47 (s, 2H), 7.29 (d, J = 5.2 Hz, 1H),7.16-7.22 (m, 1H). ESI MS m/z 328 [M − H]⁻ 119

¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (bs, 1H), 9.17 (s, 1H), 8.80 (s, 1H),7.97-8.01 (m, 1H), 7.62-7.66 (m, 1H), 7.17-7.19 (m, 1H), 2.72 (s, 3H).ESI MS m/z 327 [M − H]⁻ 120

¹H NMR (500 MHz, DMSO-d₆) δ 12.56 (d, J = 2.5 Hz, 1H), 9.12 (d, J = 3.0Hz, 1H), 8.57 (s, 1H), 8.45 (s, 1H), 7.89 (s, 1H), 7.39 (s, 2H). ESI MSm/z 378 [M − H]⁻ 121

¹H NMR (500 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.14 (s, 1H), 8.56 (s, 1H),8.30 (d, J = 2.0 Hz, 1H), 8.05 (s, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.32(dd, J = 8.5, 2.0 Hz, 1H). ESI MS m/z 344 [M − H]⁻ 123

¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (bs, 1H), 9.13 (d, J = 8.0 Hz, 1H),8.13 (d, J = 8.0 Hz, 1H), 7.27- 7.33 (m, 1H), 7.17- 7.23 (m, 1H), 2.51(s, 3H). ESI MS m/z 327 [M − H]⁻ 124

¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (bs, 1H), 9.15 (s, 1H), 8.95 (s, 1H),8.63 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.45- 7.48 (m, 1H),3.93 (s, 3H). ESI MS m/z 310 [M − H]⁻ 125

¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (bs, 1H), 9.27 (d, J = 4.8 Hz, 1H),8.66 (d, J = 2.4 Hz, 1H), 8.30- 8.33 (m, 1H), 8.24- 8.27 (m, 1H), 7.57-7.60 (m, 1H), 7.30- 7.33 (m, 2H). ESI MS m/z 247 [M − H]⁻ 126

¹H NMR (400 MHz, DMSO-d₆) 12.31 (bs, 1H), 8.91 (s, 1H), 8.24 (s, 1H),7.68 (d, J = 8.8 Hz, 1H), 7.52-7.56 (m, 1H), 7.25-7.28 (m, 1H), 2.74 (s,3H). ESI MS m/z 327 [M − H]⁻ 127

¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (bs, 1H), 9.50 (s, 1H), 9.35 (s, 1H),8.72 (d, J = 3.2 Hz, 1H), 8.37-8.40 (m, 1H), 7.56-7.59 (m, 1H),7.28-7.34 (m, 2H), 2.53 (s, 3H). ESI MS m/z 304 [M − H]⁻ 128

¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (bs, 1H), 12.43 (s, 1H), 8.83 (s, 1H),8.12 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.20-7.23 (m, 1H), 2.63 (s, 3H).ESI MS m/z 319 [M − H]⁻ 129

¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (bs, 1H), 8.67 (s, 1H), 8.20 (s, 1H),7.63 (d, J = 9.6 Hz, 1H), 7.50-7.55 (m, 1H), 7.48 (s, 2H), 7.26-7.30 (m,1H). ESI MS m/z 328 [M − H]⁻ 130

¹H NMR (400 MHz, DMSO-d₆) δ 13.36 (bs, 1H), 12.37 (s, 1H), 8.83 (s, 1H),7.87 (dd, J = 10.8, 1.6 Hz, 1H), 7.40-7.46 (m, 1H), 7.00-7.08 (m, 1H),2.63 (s, 3H). ESI MS m/z 303 [M − H^(]−) 131

¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (bs, 1H), 8.67 (s, 1H), 8.18 (s, 1H),7.93 (s, 1H), 7.48-7.56 (m, 3H), 7.36-7.40 (m, 1H). ESI MS m/z 344 [M −H]⁻ 132

¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (bs, 1H), 9.17 (s, 1H), 9.12 (s, 1H),7.96-8.00 (m, 1H), 7.62-7.67 (m, 1H), 7.15-7.22 (m, 1H), 2.48 (s, 3H).ESI MS m/z 327 [M − H]⁻ 133

¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (bs, 1H), 9.17 (s, 1H), 8.81 (s, 1H),8.30 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.32-7.35 (m, 2H), 4.08 (s, 2H),2.32 (s, 2H). ESI MS m/z 358 [M − H]⁻ 134

¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (bs, 1H), 8.58 (s, 1H), 8.01 (s, 1H),7.45 (d, J = 8.4 Hz, 1H), 7.38 (s, 2H), 7.21 (d, J = 8.4 Hz, 1H), 2.62(s, 3H). ESI MS m/z 358 [M − H]⁻ 135

¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (bs, 1H), 8.57 (s, 1H), 7.72-7.76 (m,1H), 7.39-7.45 (m, 3H), 7.04-7.06 (m, 1H), 2.62 (s, 3H). ESI MS m/z 342[M − H]⁻ 137

¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (bs, 1H), 9.14 (s, 1H), 8.90 (s, 1H),8.32-8.35 (m, 1H), 7.60-7.63 (m, 1H), 7.29-7.34 (m, 2H), 4.04 (s, 2H),1.99 (s, 2H). ESI MS m/z 326 [M + H]⁺ 138

¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (bs, 1H), 9.15 (s, 1H), 8.80 (s, 1H),8.32-8.35 (m, 1H), 7.61 (d, J = 5.6 Hz, 1H), 7.30-7.32 (m, 2H), 4.08 (s,2H), 2.23 (s, 2H). ESI MS m/z 326 [M + H]⁺ 139

¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (bs, 1H), 9.09 (d, J = 2.8 Hz, 1H),8.48 (s, 1H), 8.30-9.34 (m, 1H), 8.17 (s, 1H), 7.60 (d, J = 6.4 Hz, 1H),7.29- 7.33 (m, 2H). ESI MS m/z 334 [M − H]⁻ 140

¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (bs, 1H), 9.17 (s, 1H), 8.88 (s, 1H),8.13 (d, J = 8.0 Hz, 1H), 7.27-7.30 (m, 1H), 7.17-7.21 (m, 1H), 3.24 (q,J = 7.2 Hz, 2H), 1.15 (t, J = 7.26 Hz, 3H). ESI MS m/z 301 [M − H]⁻ 141

¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (bs, 1H), 9.22 (s, 1H), 8.95 (s, 1H),8.66 (s, 1H), 7.78~7.82 (d, J = 8.4 Hz, 1H), 7.68~7.72 (d, J = 8.4 Hz,1H), 3.93 (s, 3H). LC-MS: m/z 310.1 [M − H]⁻ 142

¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (bs, 1H), 9.13 (s, 1H), 8.86 (s, 1H),7.42 (d, J = 8.0 Hz, 1H), 7.29-7.34 (m, 1H), 7.00-7.06 (m, 1H), 3.22 (q,J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H). ESI MS m/z 301 [M − H]⁻ 143

¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (bs, 1H), 9.17 (d, J = 2.8 Hz, 1H),8.86 (s, 1H), 8.27-8.33 (m, 1H), 7.39-7.43 (m, 1H), 7.16-7.18 (m, 1H),3.24 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). ESI MS m/z 301 [M −H]⁻ 144

145

¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.91 (s, 1H), 8.12~8.15 (d, J= 7.6 Hz, 1H), 7.26~7.30 (m, 1H), 7.16~7.21 (m, 1H), 4.03 (s, 2H). LC/MS(m/z) 342.3 [M − H]− 146

¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.83 (s, 1H), 8.13~8.16 (d, J= 8.0 Hz, 1H), 7.26~7.31 (m, 1H), 7.16~7.22 (m, 1H), 4.08 (s, 2H). LC/MS(m/z) 342.4 [M − H]⁻ 147

¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (bs, 1H), 9.12 (s, 1H), 8.49 (s, 1H),8.17 (s, 2H), 7.96-8.00 (m, 1H), 7.61-7.66 (m, 1H), 7.15-7.21 (m, 1H).ESI MS m/z 352 [M − H]⁻ 148

¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (bs, 1H), 9.12 (s, 1H), 8.56 (s, 1H),7.97-8.01 (m, 1H), 7.60-7.65 (m, 1H), 7.49 (s, 2H), 7.16-7.19 (m, 1H).ESI MS m/z 328 [M − H]⁻ 149

¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (bs, 1H), 9.19 (s, 1H), 8.87 (s, 1H),8.13-8.19 (m, 1H), 7.64-7.70 (m, 1H), 3.24 (q, J = 7.2 Hz, 2H), 1.15 (t,J = 7.2 Hz, 3H). ESI MS m/z 319 [M − H]⁻ 150

¹H NMR (400 MHz, LC- MS: DMSO-d₆) δ 13.11 (bs, 1H), 9.19 (s, 1H), 8.88(s, 1H), 7.83-7.87 (m, 1H), 7.24~-7.31 (m, 1H), 3.23~3.28 (q, J = 7.2Hz, 2H), 1.13~1.18 (t, J = 7.2 Hz, 3H). m/z 318.9 [M − H]⁻ 154

¹H NMR (400 MHz, LC- MS: DMSO-d₆) δ 12.55 (bs, 1H), 9.11 (s, 1H), 8.58(s, 1H), 8.13~8.16 (m, 1H), 7.67~7.70 (m, 1H), 7.44 (s, 2H). m/z 346.0[M − H]−

Additional exemplary indole compounds are shown in Table 2 below.

TABLE 2 Additional Exemplary Indole Compounds ARI-# Structural Formula1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

1071

1072

1073

Single stereochemical isomers, enantiomers, diastereomers, andpharmaceutically acceptable salts of the above exemplified compounds arealso within the scope of the present disclosure. Pharmaceuticallyacceptable salts may be, for example, derived from suitable inorganicand organic acids and bases.

Acid addition salts can be prepared by reacting the purified compound inits free-based form, if possible, with a suitable organic or inorganicacid and isolating the salt thus formed. Examples of pharmaceuticallyacceptable acid addition salts include, without limitations, salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid.

Base addition salts can be prepared by reacting the purified compound inits acid form with a suitable organic or inorganic base and isolatingthe salt thus formed. Such salts include, without limitations, alkalimetal (e.g., sodium, lithium, and potassium), alkaline earth metal(e.g., magnesium and calcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts.

Other pharmaceutically acceptable salts include adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valeratesalts.

In some embodiments, the compound may be selected from a groupconsisting of ARI-017, ARI-018, ARI-019, ARI-020, ARI-031, ARI-060,ARI-083, ARI-087, ARI-090, ARI-118, ARI-120, ARI-140, ARI-143, ARI-145,ARI-146, ARI-148, ARI-149, or ARI-150, or an enantiomer, diastereomer,or pharmaceutically acceptable salt thereof. In some embodiments, thecompound may be selected from ARI-087, ARI-140, ARI-143, ARI-149, andARI-150, or an enantiomer, diastereomer, or pharmaceutically acceptablesalt thereof. In some embodiments, the present disclosure provides acompound selected from ARI-031, ARI-060, ARI-083, ARI-090, ARI-118,ARI-120, ARI-145, ARI-146, and ARI-148, or an enantiomer, diastereomer,or pharmaceutically acceptable salt thereof.

The indole compounds' activity in stimulating AhR can be measured by,for example, an EROD assay as described in Example 152 below. The ERODassay may be performed on, e.g., human or mouse hepatocyte cell lines.The indole compounds of the present disclosure may have an EC₅₀ of about100 nM or less (e.g., 50 nM or less, 40 nM or less, 30 nM or less, 20 nMor less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nMor less, 5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM orless, or 0.1 nM or less) in a human or mouse EROD assay.

The indole compounds' agonistic effect on AhR's immune-stimulatoryactivity may be measured by the compounds' ability to inhibit IL-21secretion from CD4⁺ T cells, as described below in Example 153. In suchan assay, the indole compounds of the present disclosure may have anIC₅₀ of about 500 nM or less (e.g., 400 nM or less, 300 nM or less, 200nM or less, 100 nM or less, 50 nM or less, 40 nM or less, 30 nM or less,20 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, or 0.1 nM orless).

The metabolic and PK profiles of the present indole compounds areexemplified in Examples 154 and 155.

The indole compounds of the present disclosure may be synthesized bymethods known in the art or by methods illustrated in Examples 1-151below.

Pharmaceutical Compositions and Use

An aspect of the present disclosure relates to pharmaceuticalcompositions comprising one or more indole compounds disclosed hereinformulated with one or more pharmaceutically acceptable excipients orcarriers (carrier system). The carrier system may include, for example,solvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, fillers, extenders, disintegrating agents, solidbinders, absorbents, lubricants, wetting agents, and the like. Thepharmaceutical compositions can be administered to patients, forexample, orally, or parenterally (e.g., subcutaneously, intravenously,or intramuscularly), intranasally, or topically. The pharmaceuticalcompositions may be provided, for example, in a form of cream, capsules,tablets, lozenges, or injectables.

Another aspect of the present disclosure relates to a method ofstimulating the immune system in a patient in need thereof, e.g., in apatient suffering from cancer or an infection (e.g., a viral, bacterial,or parasitic infection). The method includes administering to thepatient a therapeutically effective amount of one or a combination ofthe compounds described herein. In some embodiments, the patient has anincreased count of white blood cells, T and/or B lymphocytes,macrophases, dendritic cells, neutrophils, natural killer (NK) cells,and/or platelets after the administering step. In some embodiments, thecompound decreases IL-21 level in the patient. The patient may havecancer, or may be immune-compromised.

Accordingly, the present disclosure provides a method of treating cancerin a patient in need thereof, comprising administering to the patient atherapeutically effective amount of one or a combination of thecompounds described herein. In some embodiments, the patient has aliquid cancer (e.g., a hematological malignancy such as lymphoma,leukemia, and myeloma) or a solid tumor. In some embodiments, thepatient has lung cancer (e.g., nonsmall cell lung cancer), ovariancancer, cancer of the Fallopian tube, cervical cancer, breast cancer,skin cancer (e.g., melanoma), colorectal cancer, stomach cancer,pancreatic cancer, liver cancer, mesothelioma, kidney cancer (e.g.,renal cell carcinoma), bladder cancer, prostate cancer, soft tissuecancer, squamous cell carcinoma, head and neck cancer, glioma, or braintumor. This is by no means to limit the therapeutic scope of thecompounds, given their broad cancer inhibition capabilities. In someembodiments, the cancer is metastatic or otherwise advanced.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabrogating a biological disorder and/or at least one of its attendantsymptoms. As used herein, to “alleviate” a disease, disorder orcondition means reducing the severity and/or occurrence frequency of thesymptoms of the disease, disorder, or condition. Further, referencesherein to “treatment” include references to curative, palliative andprophylactic treatment. Treatment of cancer encompasses inhibitingcancer growth (including causing partial or complete cancer regression),inhibiting cancer progression or metastasis, preventing cancerrecurrence or residual disease, and/or prolonging the patient'ssurvival. “A therapeutically effective amount” is an amount of themedication that can achieve the desired curative, palliative, orprophylactic effect for the treated condition.

In some embodiments, the effective dose range of a compound isdetermined by measuring the patient's blood concentration of thecompound under a specified dosing regimen to establish aconcentration-time profile, consulting with an established correlationbetween the concentration-time profiles and effects on cancer inhibitionor eradication obtained during a trial, and balancing the therapeuticeffects achievable with possible toxicity to the patient, with furtherconsideration of the health condition or physical durability of thepatient. The dosing frequency of the compound may be determinedsimilarly. The dosing may be continued until the patiunlessent is freefrom the cancer.

In some embodiments, an effective amount for tumor therapy may bemeasured by its ability to stabilize disease progression and/orameliorate symptoms in a patient, and preferably to reverse diseaseprogression, e.g., by reducing tumor size. In some embodiments, amaintenance dosing may be provided after the patient is free of cancerto ensure its complete elimination or eradication, or prevention ofresidual disease. The duration of the maintenance dosing can bedetermined based on clinical trial data.

In some embodiments, a compound may be administered in combination withone or more other cancer therapeutic agents that also target AhR ortarget molecules other than AhR. Compounds can be formulated eitherseparately from, or together with, the other cancer therapeutic agents.Compounds can be administered either at the same schedule as, or at adifferent schedule from, the other cancer therapeutic agents. Theproportion of a compound relative to other cancer therapeutic agents maybe determined by clinical trials. Combining the compounds with the othercancer therapeutic agents may further enhance the efficacy of oneanother. For example, a compound of the present invention can beadministered with an immune checkpoint inhibitor, such as an inhibitorof PD-1, PD-L1 or PD-L2 (e.g., pembrolizumab, nivolumab, oratezolizumab), or administered with CAR-T therapy (e.g., axicabtageneciloleucel), to achieve additive or synergistic anti-cancer effect.

Dosage regimens may be adjusted to provide the optimum desired response.Dosage unit form, as used herein, refers to physically discrete unitssuited as unitary dosages for the patients/subjects to be treated; eachunit containing a predetermined quantity of active compound calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the embodied composition.Further, the dosage regimen with the compositions of this invention maybe based on a variety of factors, including the type of disease, theage, weight, sex, medical condition of the patient, the severity of thecondition, the route of administration, and the particular antibodyemployed. Thus, the dosage regimen can vary widely, but can bedetermined routinely using standard methods. For example, doses may beadjusted based on pharmacokinetic or pharmacodynamic parameters, whichmay include clinical effects such as toxic effects and/or laboratoryvalues.

It is contemplated that a suitable dose of a compound of the presentinvention may be in the range of 0.1-100 mg/kg, such as about 0.5-50mg/kg, e.g., about 1-20 mg/kg. The compound may for example beadministered in a dosage of at least 0.25 mg/kg, e.g., at least 0.5mg/kg, such as at least 1 mg/kg, e.g., at least 1.5 mg/kg, such as atleast 2 mg/kg, e.g., at least 3 mg/kg, such as at least 4 mg/kg, e.g.,at least 5 mg/kg; and e.g., up to at most 50 mg/kg, such as up to at themost 30 mg/kg, e.g., up to at the most 20 mg/kg, such as up to at themost 15 mg/kg. Administration will normally be repeated at suitableintervals, e.g., twice a day, thrice a day, once a day, once every week,once every two weeks, or once every three weeks, and for as long asdeemed appropriate by the responsible doctor, who may optionallyincrease or decrease the dosage as necessary.

Synthesis

The compounds disclosed herein can be prepared by using one or more ofthe following general synthetic schemes exemplified below. These generalsynthetic schemes as well as the examples that follow are for purposesof illustration only and are not to be construed as limiting the scopeof the invention in any manner.

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Non-commercial indole carboxylic acids wereprepared by the methods of A. S. Katner; Organic Preparations andProcedures 2(4):297-303 (1970); J Med Chem 57(17): 7293-7316 (2014); andChem. Eur. J 17(26):7298-7303 (2011). Non-commercial key intermediatesmethyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate and2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid were obtained fromthe literature preparation. The preparation of tert-butyl3-(methoxy(methyl)carbamoyl)-1H-indazole-1-carboxylate is known. SeeCrestey, Francois; Stiebing, Silvia; Legay, Remi; Collot, Valerie;Rault, Sylvain; Tetrahedron 63(2):419-428 (2007). All non-aqueousreactions were carried out under an atmosphere of dry nitrogen (unlessotherwise noted). Proton nuclear magnetic resonance spectra wereobtained on a Bruker Avance III 400 MHz NMR with autosampler, a BrukerAvance II 300 MHz NMR, or a Bruker Ascend 500 spectrometer at 500 MHz.Spectra are given in ppm (δ) and coupling constants, J values, arereported in hertz (Hz). Tetramethylsilane was used as an internalstandard for proton nuclear magnetic resonance. Mass spectra and LCMSanalyses were obtained using a Waters Acquity UPLC-H Class LC-MS systemor a Shimadzu 2020 single quadrupole mass spectrometer (DUIS, UP-LCMS).HPLC analyses were performed using a Waters Separations Module 2695/2998PDA detector.

Intermediate Preparation

Preparation 1: 2-bromo-4-((tert-butyldimethylsilyloxy)methyl)thiazole(1)

This compound was prepared according to the procedure described indocuments WO2013/163279 and Tetrahedron Lett. 1991, 32, 4263. NaBH₄(32.0 g, 0.845 mol) was added portionwise to a solution of ethyl2-bromothiazole-4-carboxylate (100.0 g, 0.424 mol) in EtOH (800 mL) over0.5 h at <50° C. with stirring. The suspension was heated under refluxfor 5 h. The mixture was cooled to room temperature and the solvent wasremoved under reduced pressure. The residue was dissolved in CH₂Cl₂ (500mL) and the resulting solution was washed with saturated aqueous NaHCO₃(300 mL×3) and brine (300 mL×1), dried over anhydrous Na₂SO₄ andconcentrated to dryness to afford the corresponding alcohol (70 g).

The alcohol was dissolved in dimethylformamide (DMF) (300 mL) andimidazole (36.8 g, 0.54 mol) was added. Then a solution of TBS-Cl (81.5g, 0.54 mol) in tetrahydrofuran (THF) (200 mL) was added dropwise atroom temperature. The reaction mixture was stirred overnight, and thenwater (100 mL) was added. The resulting mixture was extracted with EtOAc(100 mL×3). The combined organic phases were washed with aqueous 5%KHSO₄ (200 mL×3), saturated aqueous NaHCO₃ (200 mL×3) and brine (200mL×1), dried over anhydrous Na₂SO₄ and concentrated to dryness. Theresidue was purified by distillation under reduced pressure to affordcompound 1 (bp130˜140 C/13.3 pa, 96.1 g, 74% yield) as an oil.

Preparation 2: 5-fluoro-1H-indole-3-carboxylic Acid (2)

This compound was prepared according to the procedure described in theJournal of Medicinal Chemistry 2014, 57(17), 7293-7316. Trifluoroaceticanhydride (38 mL, 56.0 g, 0.27 mol) was added dropwise to a solution of5-fluoro-1H-indole (30.0 g, 0.22 mol) in DMF (300 mL) over 0.5 h at 0°C. The reaction mixture was allowed to warm to room temperature andstirred overnight. The mixture was quenched with water (1 L), afterwhich solids began to form, the mixture was stirred for 0.5 h, thenfiltered. The solid was collected, washed with water (200 mL×3), thenadded to aqueous sodium hydroxide (20%, 150 mL, 0.75 mol) and heatedunder reflux for 8 h. The reaction mixture was cooled and acidified withaqueous 3N HCl to pH of 3 whereupon a precipitate was produced. Thesolid was collected by filtration, washed with water (200 mL×3), driedto afford compound 2 (27.1 g, 68% yield) as off-white solid.

Preparation 3: 7-fluoro-1H-indole-3-carboxylic Acid (3)

This compound was synthesized according to the protocol described inPreparation 2 from 7-fluoro-1H-indole to give title compound in the formof a yellow solid (75% yield).

Preparation 4: 1H-Indole-5-methoxy-3-carboxylic Acid (4)

This compound was synthesized according to the protocol described inPreparation 2 from 5-methoxy-1H-indole to give title compound in theform of a yellow solid (65% yield).

Preparation 5: 5-Bromo-1H-Indole-3-carboxylic Acid (5)

This compound was synthesized according to the protocol described inPreparation 2 from 5-bromo-1H-indole to give title compound in the formof a yellow solid (70% yield).

Preparation 6: 6-Bromo-1H-Indole-3-carboxylic Acid (6)

This compound was synthesized according to the protocol described inPreparation 2 from 6-bromo-1H-indole to give title compound in the formof a yellow solid (55% yield).

Preparation 7: 7-Bromo-1H-Indole-3-carboxylic Acid (7)

This compound was synthesized according to the protocol described inPreparation 2 from 7-bromo-1H-indole to give title compound in the formof a yellow solid (63% yield).

Preparation 8: 5-chloro-2-methyl-1H-indole-3-carboxylic Acid (8)

This compound was prepared according to the procedure described inChemistry-A European Journal, 2011, 17(26), 7298-7303. InBr₃ (5 mg,cat.) and anhydrous MgSO₄ (24.0 g, 0.2 mol) were added to a solution of4-chloroaniline (24.0 g, 0.21 mol) and methyl acetoacetate (28.0 g, 0.24mol) in dichloromethane (DCM) (200 mL) at room temperature. The reactionmixture was stirred overnight, then filtered. The filtrate wasconcentrated to dryness. The residue was dissolved in DMF (200 mL), andPd(OAc)₂ (2.2 g, 10 mmol), Cu(OAc)₂ (110.0 g, 0.61 mol), K₂CO₃ (83.0 g,0.60 mol) were added. The resulting mixture was heated to 140° C. andstirred for 5 h. The mixture was cooled to room temperature, quenchedwith water (500 mL) and then extracted with EtOAc (300 mL×3). Thecombined organic phases were washed with water (500 mL×3), saturatedaqueous NaHCO₃ (500 mL×3) and brine (500 mL×1), dried (Na₂SO₄), filteredand then concentrated to dryness. The residue was purified by flashcolumn chromatography on silica gel (EtOAc:Hexane—1:20 to 1:10) toafford methyl 5-chloro-2-methyl-1H-indole-3-carboxylate (10.1 g, 21%yield).

The above methyl ester (10.0 g, 45 mmol) was added to aqueous sodiumhydroxide (10%, 100 mL, 0.25 mol) and heated under reflux for 8 h. Thereaction mixture was cooled and acidified with aqueous 3N HCl to a pH of3 whereupon a precipate began to form. The solid was collected byfiltration, washed with water (20 mL×3), dried to afford compound 8 (6.7g, 71% yield) as an off-white solid.

Preparation 9: 5-fluoro-2-methyl-1H-indole-3-carboxylic Acid (9)

This compound was synthesized according to the protocol described inPreparation 8 from 4-fluoroaniline to give title compound in the form ofa yellow solid (22% yield).

Preparation of the Key Intermediates Int-A, Int-B and Int-C.

The key intermediates Int-A, Int-B and Int-C were synthesized accordingto the scheme of FIG. 16 and by the following steps:

Step 1:

Oxalyl chloride (473.3 g, 3.73 mol) was added dropwise to a suspensionof indol-3-carboxylic acid (400 g, 2.48 mol) in DCM (4 L) at 0° C. over1 h. The mixture was allowed to warm to room temperature and stirredovernight. The mixture was concentrated to dryness to afford1H-indole-3-carbonyl chloride (446.0 g).

The above 1H-indole-3-carbonyl chloride (446.0 g) was added portion-wiseto a suspension of N,O-dimethylhydroxylamine hydrochloride (266.0 g,2.73 mol) and TEA (551.1 g, 5.46 mol) in DCM (5 L) at room temperatureover 1 h. The mixture was stirred overnight, then quenched with water (2L). The organic phase was collected and washed with water (2 L×2),saturated aqueous NaHCO₃ (2 L×2), and brine (2 L×1), dried (Na₂SO₄),filtered and concentrated to dryness. The residue and DMAP (15.1 g,0.124 mol) was dissolved in DMF (1 L) and DCM (4 L), cooled to 0° C.Boc₂O (540.64 g, 2.48) and DMAP (15.1 g, 0.124 mol) were added dropwiseto over 1 h.

The resulting mixture was allowed to warm to room temperature andstirred overnight. The mixture was quenched with water (2 L). Theorganic phase was separated and washed with water (2 L×2), saturatedaqueous NaHCO₃ (2 L×2), and brine (2 L×1), dried (Na₂SO₄), filtered andconcentrated to dryness. The residue was triturated with EtOAc/hexane(1:5, 1 L), filtered and dried to afford tert-butyl3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (557.9 g, 75%yield) as off-white solid. ¹H-NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H),8.22 (d, J=8.0 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 7.35-7.45 (m, 1H),7.30-7.35 (m, 1H), 3.74 (s, 3H), 3.32 (s, 3H), 1.67 (s, 9H).

Step 2:

A solution of 2-bromo-4-((tert-butyldimethylsilyloxy)methyl)thiazole(135.0 g, 0.44 mol) in THF (1.5 L) was cooled to −78° C., and n-BuLi(1.6 M solution in hexane, 385 mL, 0.62 mol) was added dropwise at −78°C. over 1 h. The mixture was stirred for 0.5 h at this temperature, thena solution of tert-butyl3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (120.0 g, 0.4 mol)in THF (500 mL) was added dropwise over 1 h. The mixture was stirred at−78° for 1 h then allowed to warm to 0° C. and quenched with aqueous 10%NH₄Cl (1 L). The organic phase was collected and washed with water (1L×2), saturated aqueous NaHCO₃ (1 L×2), and brine (1 L×1), dried(Na₂SO₄), filtered and concentrated to dryness. The residue wastriturated with EtOAc/hexane (1:5, 500 mL), filtered and dried to affordtert-butyl3-(4-((tert-butyldimethylsilyloxy)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(132.0 g, 70% yield) as off-white solid. ¹H-NMR (400 MHz, DMSO-d6): δ9.42 (bs, 1H), 8.39 (d, J=7.6 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.01 (s,1H), 7.40-7.52 (m, 2H), 4.93 (s, 2H), 1.69 (s, 9H), 0.92 (s, 9H), 0.14(s, 6H).

Step 3:

A solution of tert-butyl3-(4-((tert-butyldimethylsilyloxy)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(91.0 g, 0.19 mol) in THF (500 mL) and pyridine (50 mL) was cooled to 0°C., and HF-pyridine (30%, 50 mL) was added dropwise over 10 min. Themixture was stirred for 0.5 h at this temperature, then allowed to warmto room temperature and stirred overnight. The mixture was quenched withaqueous 10% NH₄Cl (1 L) and EtOAc (500 mL). The organic phase wascollected and washed with water (500 mL×2), saturated aqueous NaHCO₃(500 mL×2), and brine (500 mL×1), dried (Na₂SO₄), filtered andconcentrated to dryness. The residue was triturated with EtOAc/hexane(1:5, 100 mL), filtered and dried to afford tert-butyl3-(4-(hydroxymethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate (49.6g, 73% yield) as off-white solid. ¹H-NMR (400 MHz, DMSO-d6): δ 9.43 (s,1H), 8.35-8.40 (m, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.42-7.50(m, 2H), 5.5557 (t, J=5.6 Hz, 1H), 4.75 (d, J=5.6 Hz, 2H), 1.99 (s, 9H).ESI MS: m/z 359 [M+H]⁺.

Step 4:

To a mixture of tert-butyl3-(4-(hydroxymethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate (1.9 g,5.30 mmol) in DCM (53.0 ml) in a water bath was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (2.473 g,5.83 mmol). After 1 h, saturated NaHCO₃ (aq) and 10% Na₂S₂O₃ (aq) wereadded then the mixture stirred for 30 min. The layers were separated andthe organic phase was washed with bicarbonate, dried (Na₂SO₄), filteredand concentrated. Chromatography (silica gel, heptane to CH₂Cl₂) gavetert-butyl 3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (1.63g) as a white solid. ESI MS m/z 357 [M+H]⁺.

Step 5:

A solution of NaClO₂ (19.0 g, 210 mmol) and KH₂PO₄ (46.7 g, 0.336 mmol)in H₂O (200 mL) was added dropwise to a solution of tert-butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (15.0 g, 42mmol) in tBuOH/H₂O/DCM (300 mL/60 mL/60 mL) at room temperature over 0.5h. The mixture was stirred for 5 h. The mixture was extracted with EtOAc(300 mL×4), the combined organic phases were washed with aqueous 5%KHSO₄ (500 mL×3) and brine (500 mL×1), dried (Na₂SO₄), filtered andconcentrated to dryness. The residue was triturated with EtOAc/hexane(1:2, 50 mL), filtered and dried to afford2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (13.5 g, 86% yield) as off-white solid. ¹H-NMR (400 MHz, DMSO-d6):δ 13.48 (bs, 1H), 9.62 (s, 1H), 8.89 (s, 1H), 8.38 (m 1H), 8.18 (d,J=8.0 Hz, 1H), 7.48 (m, 2H), 1.69 (s, 9H). ESI MS m/z 371 [M−H]⁻.

Alternate Preparation of the Key Intermediate Int-B.

To a suspension of methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate(5.00 g, 17.46 mmol) and di-tert-butyl dicarbonate (5.27 ml, 22.70 mmol)in acetonitrile (175 ml) was added DMAP (0.640 g, 5.24 mmol). Uponcompletion, the reaction mixture was concentrated. Chromatography(silica gel, 1% to 10% MeOH in DCM) gave methyl2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylate(6.30 g) as an off white solid. ESI MS m/z 373 [M+H]⁺.

Preparation of the Key Intermediate Int-E.

The key intermediate Int-E was synthesized according to the scheme ofFIG. 17 and by the following method.

To a suspension of methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate(200 mg, 0.699 mmol) and di-tert-butyl dicarbonate (198 mg, 0.908 mmol)in acetonitrile (69860) was added 4-(dimethylamino)pyridine (25.6 mg,0.210 mmol). Upon completion, the reaction solvent was concentrated.Chromatography (silica gel, heptane to % MeOH/CH₂Cl₂) gave methyl2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylate(269 mg) as a white solid. ESI MS m/z 387 [M+H]⁺.

The following Examples and FIGS. 1-64 are meant to illustrate thesynthesis and use of the present indole compounds and should not beconstrued as limiting the present disclosure in any manner.

EXAMPLES Example 1: Preparation of methyl2-(1H-indole-3-carbonothioyl)thiazole-4-carboxylate (ARI-007)

Methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (0.200 g, 0.699mmol) and Lawesson's Reagent (0.113 g, 0.279 mmol) in THF (6.99 ml) werecombined and the mixture heated to 65° C. Upon completion, the reactionwas concentrated onto silica gel. Chromatography (silica gel, 0 to 100%heptane to ethyl acetate) followed by reverse phase chromatography (C18,10% ACN/H₂O to ACN) gave methyl2-(1H-indole-3-carbonothioyl)thiazole-4-carboxylate (75 mg) as a brownsolid.

Example 2: Preparation of (4-bromothiazol-2-yl)(1H-indol-3-yl)methanone(ARI-008)

Step 1.

Conducted by analogy to Org. Lett. 2016, 18, 3918-3921. To a solution of1H-indole (360 mg, 3.07 mmol) in 3 mL of anhydrous THF was addedpotassium tert-butoxide (1 M in THF) (3.38 mL, 3.38 mmol). Afterstirring for 30 min, triethylborane (1 M in hexanes) (3.38 mL, 3.38mmol) was added. After 30 min, the solution was cannulated slowly intoan ice-cold mixture of 4-bromothiazole-2-carbonyl chloride (763 mg, 3.37mmol) in THF (3 mL). Upon completion, the reaction was quenched withsaturated NH₄Cl (aq). This mixture was extracted 3× with EtOAc. Thecombined organics were dried over Na₂SO₄, filtered and concentrated.Chromatography (silica gel, heptane to 10% MeOH/CH₂Cl₂) gave(4-bromothiazol-2-yl)(1H-indol-3-yl)methanone (760 mg) as an impureorange solid. ESI MS m/z 307 [M+H]⁺.

Step 2.

To a suspension of (4-bromothiazol-2-yl)(1H-indol-3-yl)methanone (0.218g, 0.710 mmol) and di-tert-butyl dicarbonate (0.214 ml, 0.923 mmol) inacetonitrile (7.10 ml) was added DMAP (0.026 g, 0.213 mmol). Uponcompletion, the reaction mixture was concentrated under reduced pressureonto silica gel. Chromatography (silica gel, 0 to 50% DCM/heptane) gavetert-butyl 3-(4-bromothiazole-2-carbonyl)-1H-indole-1-carboxylate (0.177g) as a white solid. ESI MS m/z 407 [M+H]⁺.

Step 3.

To a solution of tert-butyl3-(4-bromothiazole-2-carbonyl)-1H-indole-1-carboxylate (0.100 g, 0.246mmol) in dichloromethane (2.5 ml) was added trifluoroacetic acid (TFA)(0.500 ml). Upon completion, the reaction mixture was concentrated.Chromatography (silica gel, heptane to 40% ethyl acetate/heptane) gave(4-bromothiazol-2-yl)(1H-indol-3-yl)methanone (0.060 g) as a yellowsolid.

Example 3: Preparation of methyl(2-(1H-indole-3-carbonyl)thiazol-4-yl)carbamate (ARI-009)

Triethylamine (0.410 ml, 2.94 mmol) and diphenylphosphoryl azide (0.950ml, 4.41 mmol) were added to an ice-cold mixture of2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid (0.400 g, 1.469 mmol)in dioxane (2.94 ml) at 0° C. After 15 min, the ice bath was removedthen methanol (16 ml, 395 mmol) was added dropwise over 10 minutes oncegas evolution had ceased. The reaction mixture was stirred overnight.Water was added and the mixture was extracted with ethyl acetate 2×75mL, then washed with brine, dried over sodium sulfate, filtered andconcentrated onto silica gel. Chromatography (silica gel, heptane to 50%ethyl acetate/heptane) gave methyl(2-(1H-indole-3-carbonyl)thiazol-4-yl)carbamate (0.021 g) as a yellowsolid.

Example 4: Preparation of methyl2-((1H-indol-3-yl)(methoxyimino)methyl)thiazole-4-carboxylate (ARI-011)

A mixture of 2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid (314 mg,1.153 mmol) and O-methylhydroxylamine hydrochloride (450 mg, 5.39 mmol)in MeOH was heated in a microwave to 140° C. for 30 min. Uponcompletion, the mixture was concentrated to dryness. Chromatography(silica gel, heptane to DCM then to 10% MeOH/DCM) gave methyl241H-indol-3-yl)(methoxyimino)methyl)thiazole-4-carboxylate (163.8, mg)as a mixture of E/Z isomers and as an orange solid after lyophilizationfrom acetonitrile/H₂O.

Example 5: Preparation of S-methyl2-(1H-indole-3-carbonyl)thiazole-4-carbothioate (ARI-013)

To a suspension of 2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid(0.500 g, 1.836 mmol) and di-tert-butyl dicarbonate (0.554 ml, 2.387mmol) in acetonitrile (18.36 ml) was added DMAP (0.067 g, 0.551 mmol)and triethylamine (0.256 ml, 1.836 mmol). After consumption of startingmaterial, sodium methyl mercaptide (0.167 g, 2.387 mmol) was added andthe reaction mixture stirred overnight. The reaction mixture was thenconcentrated under reduced pressure and redissolved in EtOAc, thenwashed with saturated NH₄Cl. The organic layer was dried over magnesiumsulfate, then absorbed onto silica gel. Chromatography (silica gel, 12g, solid load, 0-80% CH₂Cl₂/heptane) gave tert-butyl3-(4-((methylthio)carbonyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(0.21 g, 0.522 mmol, 28.4% yield). ESI MS: m/z 403 [M+H]+.

To a solution of tert-butyl3-(4-((methylthio)carbonyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(0.207 g, 0.514 mmol) in DCM (4 ml) was added TFA (1.8 ml). Uponcompletion, the reaction mixture was concentrated under reduced pressureand precipitated overnight from methanol to give S-methyl2-(1H-indole-3-carbonyl)thiazole-4-carbothioate (0.116 g).

Example 6: Preparation of methyl2-((hydroxyimino)(1H-indol-3-yl)methyl)thiazole-4-carboxylate (ARI-014)

Methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (0.300 g, 1.048mmol) and hydroxylamine hydrochloride (0.218 g, 3.14 mmol) were combinedwith pyridine (11 ml). The reaction mixture was sealed and heated in themicrowave at 130° C. Upon completion, the reaction mixture wasconcentrated onto silica gel. Chromatography (DCM to 1% MeOH/DCM) gavemethyl 2-((hydroxyimino)(1H-indol-3-yl)methyl)thiazole-4-carboxylate(214.1, mg) as a yellow glass and as a mixture of E/Z isomers.

Example 7: Preparation of methyl2-(1-methyl-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-015)

To a suspension of methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate(111 mg, 0.388 mmol) in ice-cold THF (3877 μl) was added potassiumhexamethyldisilazide (0.5 M in toluene) (814 μl, 0.407 mmol). DMF (500uL) was added to improve solubility, the mixture stirred 10 min, theniodomethane (25.3 μl, 0.407 mmol) was added. The reaction mixture wasquenched by the addition of anhydrous MeOH, then concentrated todryness. Chromatography (silica gel, CH₂Cl₂ to 1% MeOH/CH₂Cl₂) gavemethyl 2-(1-methyl-1H-indole-3-carbonyl)thiazole-4-carboxylate (66.7 mg)as a pale orange solid.

Example 8: Preparation of methyl(S)-2-(1H-indole-3-carbonyl)-5,5-dimethyl-4,5-dihydrothiazole-4-carboxylatecarboxylate(ARI-016)

Step 1.

1H-indole-3-carbonyl cyanide (213 mg, 1.252 mmol) and(S)-2-amino-3-mercapto-3-methylbutanoic acid (187 mg, 1.252 mmol) werecombined with DMF (12 mL) then the mixture treated with1,8-diazabicyclo[5.4.0]undec-7-ene (18.72 μl, 0.125 mmol). The reactionmixture was heated to 40° C. Chromatography (silica gel, heptane toEtOAc+0.1% AcOH) gave(S)-2-(1H-indole-3-carbonyl)-5,5-dimethyl-4,5-dihydrothiazole-4-carboxylicacid (97 mg) as a white solid, ESI MS m/z 303 [M+H]⁺. Treatment of thesolid with sodium methoxide (16.97 mg, 0.314 mmol) in MeOH (10 ml) gavesodium(S)-2-(1H-indole-3-carbonyl)-5,5-dimethyl-4,5-dihydrothiazole-4-carboxylateafter the solvent was removed to dryness. The material was used as is.

Step 2.

To a solution of sodium(S)-2-(1H-indole-3-carbonyl)-5,5-dimethyl-4,5-dihydrothiazole-4-carboxylate(102 mg, 0.314 mmol) in DMF (6280 μl) was added iodomethane (19.55 μl,0.314 mmol). After the reaction was complete, the reaction wasconcentrated to dryness, then partitioned between EtOAc and water. Theorganic layer was dried with brine, filtered and concentrated.Chromatography (silica gel, CH₂Cl₂ to 6% MeOH/CH₂Cl₂) gave methyl(S)-2-(1H-indole-3-carbonyl)-5,5-dimethyl-4,5-dihydrothiazole-4-carboxylatecarboxylate(48.7 mg) as a light yellow solid.

Example 9: Preparation of methyl2-(1-(1H-indol-3-yl)-2-methoxyvinyl)thiazole-4-carboxylate (ARI-017)

Step 1.

To an ice-cold solution of (methoxymethyl)triphenylphosphonium chloride(322 mg, 0.939 mmol) in THF (8 mL) was added potassiumhexamethyldisilazide (0.5 M in toluene) (1.708 mL, 0.854 mmol). After 30min, solid methyl2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylate(300 mg, 0.776 mmol) was added then allowed to slowly warm to roomtemperature. Upon completion, saturated NH₄Cl was added then after 15min the reaction mixture was partitioned between EtOAc and saturatedNH₄Cl. The organic layer was dried with brine and Na₂SO₄, and filtered.Chromatography (silica gel, heptane to 25% EtOAc/heptane) gave methyl2-(1-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)-2-methoxyvinyl)thiazole-4-carboxylate(276.9 mg) as a pale yellow solid. ESI MS m/z 415 [M+H]⁺.

Step 2.

A mixture of methyl2-(1-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)-2-methoxyvinyl)thiazole-4-carboxylate(80 mg, 0.193 mmol) and K₂CO₃ (53.4 mg, 0.386 mmol) was stirred in MeOH(10 mL) with heating to 50° C. The reaction mixture was concentrated.Chromatography (silica gel, CH₂Cl₂ to 5% MeOH/CH₂Cl₂) gave methyl2-(1-(1H-indol-3-yl)-2-methoxyvinyl)thiazole-4-carboxylate (5.7, mg) asan off-white solid and as a mixture of E/Z isomers.

Example 10: Preparation of methyl2-(1-(1H-indol-3-yl)prop-1-en-1-yl)thiazole-4-carboxylate (ARI-018)

Prepared according to the method described in Example 9 except that(ethyl)triphenylphosphonium bromide was used instead of(methoxymethyl)triphenylphosphonium chloride.

Example 11: Preparation of methyl2-(1-(1H-indol-3-yl)vinyl)thiazole-4-carboxylate (ARI-019)

Prepared according to the method described in Example 9 except thatmethyltriphenylphosphonium bromide was used instead of(methoxymethyl)triphenylphosphonium chloride.

Example 12: Preparation of methyl2-(1-(1H-indol-3-yl)-2-methylprop-1-en-1-yl)thiazole-4-carboxylate(ARI-020)

Prepared according to the method described in Example 9 except thatisopropyltriphenylphosphonium iodide was used instead of(methoxymethyl)triphenylphosphonium chloride.

Example 13: Preparation ofN-(2-(1H-indole-3-carbonyl)thiazol-4-yl)acetamide (ARI-021)

Step 1.

Diphenylphosphoryl azide (0.231 ml, 1.071 mmol) was added to a solutionof 2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (0.266 g, 0.714 mmol) and triethylamine (0.199 ml, 1.429 mmol) inDMF (40 ml) at ambient temperature, then stirred for 30 min. After thistime, water (2 ml) was added and the resulting mixture was heated to 80°C. for one hour. The reaction mixture was cooled to ambient temperature,and water was added (50 mL), and the resulting mixture was thenextracted with ethyl acetate (3×50 mL). The organic layers were pooled,washed with brine, and dried over sodium sulfate, then filtered andconcentrated onto silica gel under reduced pressure. Chromatography(silica gel, heptane to 30% ethyl acetate/heptane) gave tert-butyl3-(4-aminothiazole-2-carbonyl)-1H-indole-1-carboxylate (0.116 g). ESI MSm/z 344 [M+H]⁺.

Step 2.

Acetyl chloride (0.025 ml, 0.352 mmol) was added to an ice-cold solutionof tert-butyl 3-(4-aminothiazole-2-carbonyl)-1H-indole-1-carboxylate(0.110 g, 0.320 mmol) and triethylamine (0.067 ml, 0.480 mmol) indichloromethane (21 ml). Upon completion, potassium carbonate (0.144 g,0.320 mmol) and methanol (10.50 ml) were added to remove the Boc group.Upon completion, water was added to the reaction and the mixtureextracted with ethyl acetate. The organic was washed with brine wash,dried over magnesium sulfate, filtered and the crude was concentratedonto silica gel. Chromatography (silica gel, heptane to 80% ethylacetate/heptane) gave N-(2-(1H-indole-3-carbonyl)thiazol-4-yl)acetamide(44.2 mg).

Example 14: Preparation of 3-hydroxypropyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-022)

To an ice-cold solution of 2-(1H-indole-3-carbonyl)thiazole-4-carboxylicacid (0.300 g, 1.102 mmol) and 4-(dimethylamino)pyridine (0.013 g, 0.110mmol) in tetrahydrofuran (11.02 ml) was sequentially added triethylamine(0.192 ml, 1.377 mmol), 1,3-propanediol (0.735 ml, 11.02 mmol), and3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (0.232 g, 1.212 mmol). The reaction mixture was warmed toambient temperature and stirred. Upon completion, 1M HCl (aq) was addedand the subsequent mixture extracted with EtOAc. The combined organicswere washed with water, sodium bicarbonate and brine. The crude wasfiltered and concentrated onto silica gel. Chromatography (silica gel,DCM to 5% MeOH/DCM) gave 3-hydroxypropyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (0.126 g) as a yellowsolid.

Example 15: Preparation of 2-hydroxyethyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-023)

Prepared according to the method described in Example 14 except thatethylene glycol was used instead of 1,3-propanediol.

Example 16: Preparation of methyl2-((1H-indol-3-yl)(methoxy)methyl)thiazole-4-carboxylate (ARI-024)

Sodium borohydride (0.092 g, 2.445 mmol) was added portionwise to amixture of methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (0.200g, 0.699 mmol) in tetrahydrofuran (6.99 mL) and methanol (6.99 mL). Uponcompletion, the reaction mixture was quenched with 1M HCl then extractedwith DCM. The organic was washed with brine, and dried over sodiumsulfate then filtered. Chromatography (silica gel, DCM to 5% MeOH/DCM)gave methyl 2-((1H-indol-3-yl)(methoxy)methyl)thiazole-4-carboxylate(0.035 g) as a pink solid.

Example 17: Preparation of 2-(2-hydroxyethoxy)ethyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-025)

Prepared according to the method described in Example 14 except thatdiethylene glycol was used instead of 1,3-propanediol.

Example 18: Preparation of2-(1H-indole-3-carbonyl)thiazole-4-carbonitrile (ARI-026)

Triethylamine (2.57 ml, 18.43 mmol) was added to an ice-cold suspensionof 2-(1H-indole-3-carbonyl)thiazole-4-carboxamide (see WO2018121434A1)(1.00 g, 3.69 mmol) in tetrahydrofuran (36.9 ml). Subsequentlytrifluoroacetic anhydride (1.302 ml, 9.22 mmol) was added dropwise. Theice bath was removed. Upon completion, the reaction mixture was pouredover ice and diluted with ethyl acetate. The organic layer was washedwith 2M Na₂CO₃ and brine, dried over sodium sulfate, filtered andconcentrated onto silica gel. Chromatography (silica gel, heptane to 50%EtOAc/heptane) gave 2-(1H-indole-3-carbonyl)thiazole-4-carbonitrile(0.720 g) as a yellow solid.

Example 19: Preparation of(4-(1,3-dioxolan-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (ARI-028)

To a solution of tert-butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (0.200 g, 0.561mmol) and ethylene glycol (0.094 ml, 1.684 mmol) in dioxane (5.61 ml)was added p-toluenesulfonic acid monohydrate (1.067 mg, 5.61 μmol) andthe mixture heated to 50° C. Upon completion, potassium carbonate (0.116g, 0.842 mmol) and MeOH was added to remove the Boc group. Uponcompletion, water was added and the pH of the solution was adjusted to 8with 1M HCl. The mixture was extracted with ethyl acetate and theorganic layer was washed with brine, then concentrated onto silica gel.Chromatography (silica gel, heptane to 50% EtOAc/heptane) gave(4-(1,3-dioxolan-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (73.4 mg) asa yellow solid.

Example 20: Preparation of(4-(dimethoxymethyl)thiazol-2-yl)(1H-indol-3-yl)methanone (ARI-029)

Prepared according to the method described in Example 19 except thatmethanol was used instead of ethylene glycol.

Example 21: Preparation of(1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(ARI-030)

A mixture of 2-(1H-indole-3-carbonyl)thiazole-4-carbonitrile (50 mg,0.197 mmol), K₃PO₄ (126 mg, 0.592 mmol) and hydroxylamine hydrochloride(34.3 mg, 0.494 mmol) in DMF (2.5 ml) was heated to 100° C. with amicrowave for 30 min. Acetyl chloride (0.028 ml, 0.395 mmol) was addedand the reaction heated to 110° C. for 2 hr. The DMF was removed underhigh vacuum. Added water, sonicated then collected the solid byfiltration. The solid was rinsed with H₂O, then dried at 50° C. underhigh vacuum to give(1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(34 mg) as a yellow solid.

Example 22: Preparation of(1H-indol-3-yl)(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)methanone(ARI-031)

Step 1.

To 2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (200 mg, 0.537 mmol), N-hydroxyacetamidine (39.8 mg, 0.537 mmol)and triethylamine (299 μl, 2.148 mmol) in ethyl acetate (2685 μl) wasadded 1-propanephosphonic acid cyclic anhydride (50 wt % in EtOAc) (799μl, 1.343 mmol) dropwise. The mixture was heated to 80° C. Uponcompletion, saturated NaHCO₃ (aq) was added and the solid collected byfiltration. Washed the solid with H₂O, and then with a minimum of EtOAc.The solid was dried under high vacuum at 50° C. to give tert-butyl3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylateas an off-white solid. ESI MS m/z 411 [M+H]⁺.

Step 2.

To tert-butyl3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(99 mg, 0.241 mmol) was added K₂CO₃ (33.3 mg, 0.241 mmol) and MeOH (5ml). Upon reaction completion, silica gel was added and the mixtureconcentrated. Chromatography (silica gel, heptane to 40% EtOAc/heptane)gave(1H-indol-3-yl)(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)methanone(64 mg) as a yellow solid after drying overnight at 50° C. in the vacuumoven.

Example 23: Preparation of methyl 6-(1H-indole-3-carbonyl)picolinate(ARI-032)

Prepared according to the method described in Example 2 except thatmethyl 6-(chlorocarbonyl)picolinate hydrochloride was used instead of4-bromothiazole-2-carbonyl chloride in step 1 and the Boc deprotectionwas effected as follows. Methyl 6-(1H-indole-3-carbonyl)picolinate (1197mg, 4.27 mmol) was treated with sodium sulfate (606 mg, 4.27 mmol) andstirred in anhydrous MeOH (50 ml) for 30 min then K₂CO₃ (177 mg, 1.281mmol) was added. Upon completion, the mixture was filtered throughCelite, silica gel was added and concentrated to dryness. Chromatography(silica gel, heptane to EtOAc) and then reverse phase (C18, H₂O toCH₃CN) gave methyl 6-(1H-indole-3-carbonyl)picolinate as an off-whitesolid.

Example 24: Preparation ofN-ethyl-2-(1H-indole-3-carbonyl)thiazole-4-carboxamide (ARI-033)

Propylphosphonic anhydride (0.352 ml, 0.591 mmol, 50 wt % in EtOAc) wasadded to a solution of2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (0.200 g, 0.537 mmol), ethanamine (0.322 ml, 0.644 mmol), and DIPEA(0.141 ml, 0.806 mmol) in N,N-dimethylformamide (5.37 ml). Uponcompletion, the Boc group was removed by adding potassium carbonate(0.300 g, 2.171 mmol) and 10 mL of MeOH and heating the mixture to 50°C. Upon completion, the mixture was concentrated under reduced pressurethen to it added 20 mL of water, followed by neutralization with 1M HClto pH 7. This mixture was extracted with 3×40 mL ethyl acetate. Thecombined organic layers were washed with 50 mL of 5% LiCl and brine,then concentrated under reduced pressure onto silica gel. Chromatography(silica gel, DCM to 5% MeOH/DCM) gaveN-ethyl-2-(1H-indole-3-carbonyl)thiazole-4-carboxamide (89.5 mg) as ayellow solid.

Example 25: Preparation of2-(1H-indole-3-carbonyl)-N-isopropylthiazole-4-carboxamide (ARI-034)

Prepared according to the method described in Example 24 except thatisopropylamine was used instead of ethylamine.

Example 26: Preparation of2-(1H-indole-3-carbonyl)-N-isobutylthiazole-4-carboxamide (ARI-035)

Prepared according to the method described in Example 24 except thatisobutylamine was used instead of ethylamine.

Example 27: Preparation ofN-(2-hydroxyethyl)-2-(1H-indole-3-carbonyl)thiazole-4-carboxamide(ARI-036)

To a solution of 2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid(0.200 g, 0.735 mmol) and hexafluorophosphate azabenzotriazoletetramethyl uronium (HATU) (0.335 g, 0.881 mmol) inN,N-dimethylformamide (7.35 ml) was added N,N-diisopropylethylamine(DIPEA) (0.385 ml, 2.204 mmol) and then ethanolamine (0.222 ml, 3.67mmol). Upon completion, water was added and the reaction mixture wasconcentrated under reduced pressure to remove DMF. The reaction mixturewas partitioned between EtOAc and H₂O. The organic phase wassuccessively washed with 1M HCl, H₂O, saturated NaHCO₃, and brine, thendried over Na₂SO₄. After filtration, the crude solution was concentratedonto silica gel. Chromatography (DCM to 25% 80:18:2 CH₂Cl₂/MeOH/conc.NH₄OH) gaveN-(2-hydroxyethyl)-2-(1H-indole-3-carbonyl)thiazole-4-carboxamide (0.164g) as a yellow solid.

Example 28: Preparation of2-(1H-indole-3-carbonyl)-N-(2-methoxyethyl)thiazole-4-carboxamide(ARI-037)

Prepared according to the method described in Example 27 except that2-methoxyethan-1-amine was used instead of ethanolamine.

Example 29: Preparation of methyl2-(1-cyano-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-038)

Cyanogen bromide (0.740 g, 6.99 mmol) was added to an ice cold solutionof methyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (0.500 g, 1.746mmol) and cesium carbonate (0.683 g, 2.096 mmol) in acetonitrile (17.46ml). The reaction suspension was filtered and rinsed with acetonitrile.The filtrate was concentrated under reduced pressure and then treatedwith boiling DCM and filtered. The filtrate was directly loaded onto asilica gel column. Chromatography (heptane to 50% EtOAc/heptane) gavemethyl 2-(1-cyano-1H-indole-3-carbonyl)thiazole-4-carboxylate (0.046 g)as a white solid.

Example 30: Preparation ofN-(tert-butyl)-2-(1H-indole-3-carbonyl)thiazole-4-carboxamide (ARI-039)

Prepared according to the method described in Example 24 except thattert-butylamine was used instead of ethylamine.

Example 31: Preparation of1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)pyrrolidine-2,5-dione (ARI-040)

To a mixture of (4-bromothiazol-2-yl)(1H-indol-3-yl)methanone (217 mg,0.533 mmol) and succinimide (79 mg, 0.799 mmol) in2,4,6-trimethylpyridine (1 ml, 0.533 mmol) was added cuprous oxide (45.7mg, 0.320 mmol). The mixture was then heated in a microwave to 175° C.for 7 hrs. The mixture was diluted with CH₂Cl₂ and then 5% H₂SO₄ (aq)was added. The solid was removed by filtration. The filtrate was treatedwith 5% H₂SO₄ (aq) then extracted with 2× with CH₂Cl₂. The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated.Chromatography (silica gel, DCM to 1% MeOH/DCM, dry loaded on Celite)gave 1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)pyrrolidine-2,5-dione (7mg) as a yellow solid.

Example 32: Preparation of(2-(1H-indole-3-carbonyl)thiazol-4-yl)(azetidin-1-yl)methanone (ARI-044)

Prepared according to the method described in Example 27 except thatazetidine hydrochloride was used instead of ethanolamine.

Example 33: Preparation of(2-(1H-indole-3-carbonyl)thiazol-4-yl)(3-methoxyazetidin-1-yl)methanone(ARI-046)

Prepared according to the method described in Example 27 except that3-methoxyazetidine hydrochloride was used instead of ethanolamine.

Example 34: Preparation of 6-(1H-indole-3-carbonyl)-N-methylpicolinamide(ARI-047)

Step 1.

Sodium hydroxide (0.813 ml, 0.813 mmol) was added to a stirring solutionof methyl 6-(1H-indole-3-carbonyl)picolinate (0.228 g, 0.813 mmol) intetrahydrofuran (4.5 ml) and water (3.7 ml). Upon completion, thereaction mixture was diluted with water and extracted with 30 mL ofEtOAc to remove unreacted ester. The aqueous layer was adjusted to pH 5with 1M HCl, then extracted with EtOAc. The organic was washed withbrine and dried over Na₂SO₄, and filtered. The crude was concentratedonto silica gel. Chromatography (C18, H₂O to 60% ACN/water) gave6-(1H-indole-3-carbonyl)picolinic acid (0.185 g, 0.695 mmol, 85% yield)as a yellow solid. ESI MS m/z 267 [M+H]⁺.

Step 2.

Prepared according to the method described in Example 27 except thatmethylamine in THF was used instead of ethanolamine.

Example 35: Preparation of2-(hydrazinylidene(1H-indol-3-yl)methyl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazole(ARI-050)

Step 1.

To a mixture of2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (60 mg, 0.161 mmol), ammonium chloride (60.3 mg, 1.128 mmol), HOBt(37.0 mg, 0.242 mmol), and ethylene dichloride (EDC) (93 mg, 0.483 mmol)was added N,N-dimethylformamide (1.6 mL) and then DIPEA (0.169 mL, 0.967mmol). Upon completion, the reaction mixture was diluted with water andsaturated NaHCO₃. The precipitate was collected, washed with water, anddried in vacuo to provide tert-butyl3-(4-carbamoylthiazole-2-carbonyl)-1H-indole-1-carboxylate (56.6 mg,0.152 mmol) as a yellow solid. ESI MS m/z 372 [M+H]⁺.

Step 2.

A mixture of tert-butyl3-(4-carbamoylthiazole-2-carbonyl)-1H-indole-1-carboxylate (56.6 mg,0.152 mmol) and 1,1-dimethoxy-N,N-dimethylethane-1-amine (1.0 mL, 6.84mmol) was stirred at 80° C. Upon completion, the reaction mixture wascooled to room temperature and concentrated to a dark brown viscous oil.The oil was dissolved in acetic acid (1.0 ml) then hydrazine hydrate (24μL, 0.762 mmol) was added. The reaction mixture was stirred at 80° C.for 1 h. The reaction mixture was concentrated to dryness.Chromatography (C18, H₂O to 60% MeCN) gave2-(hydrazinylidene(1H-indol-3-yl)methyl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazole(18 mg) as a yellow solid.

Example 36: Preparation of(4-ethynylthiazol-2-yl)(1H-indol-3-yl)methanone (ARI-052)

To a stirred solution of tert-butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (71 mg, 0.200mmol) in anhydrous methanol (2.0 mL) was added K₂CO₃ (55.3 mg, 0.400mmol) followed by dimethyl (1-diazo-2-oxopropyl)phosphonate (53.8 mg,0.280 mmol). Upon completion, the reaction mixture was concentrated todryness. The residue was treated with brine and EtOAc. Organic layer wasseparated and the aqueous layer was extracted twice with EtOAc. Thecombined organic layers were dried (Na₂SO₄), filtered, and concentrated.Chromatography (silica gel, heptane to 50% EtOAc/heptane) gave(4-ethynylthiazol-2-yl)(1H-indol-3-yl)methanone (28 mg) as a yellowsolid.

Example 37: Preparation of methyl2-(1H-indazole-3-carbonyl)thiazole-4-carboxylate (ARI-053)

To a −78° C. suspension of methyl 2-bromothiazole-4-carboxylate (0.775g, 3.49 mmol) in THF (8.19 ml) was added iPrMgCl—LiCl (1.3 M in THF)(2.52 ml, 3.28 mmol). After 15 min, a solution of tert-butyl3-(methoxy(methyl)carbamoyl)-1H-indazole-1-carboxylate (1.0 g, 3.28mmol) in THF (8.19 ml) was added dropwise to the wine colored Grignard.After 1.5 hrs, 1 N HCl (aq) was added with the bath temperature held at−10° C. The mixture was extracted with EtOAc then washed with saturatedNaHCO₃ (aq), and brine, dried (Na₂SO₄), filtered and concentrated to asolid. Chromatography (silica gel, heptane to 20% EtOAc/heptane) gaveimpure methyl2-(1-(tert-butoxycarbonyl)-1H-indazole-3-carbonyl)thiazole-4-carboxylate(317 mg, 0.818 mmol). To remove the Boc group, this was treated withanhydrous MeOH (10 mL) and then K₂CO₃ (113 mg, 0.818 mmol) was added.Upon reaction completion, 1 N HCl was added to acidify then the mixturewas extracted with EtOAc. The extract was washed with saturated sodiumbicarbonate then brine, dried over Na₂SO₄, filtered and concentrated.Chromatography (C18, H₂O to CH₃CN both with 0.1% TFA modifier) gave asolid that was triturated with hot MeOH then dried under vacuum at 50°C. to give methyl 2-(1H-indazole-3-carbonyl)thiazole-4-carboxylate (64,mg) as a yellow solid.

Example 38: Preparation of(4-(1,3,4-oxadiazol-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (ARI-056)

Step 1.

A solution of2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (200 mg, 0.537 mmol) and carbonyldiimidazole (113 mg, 0.698 mmol)in tetrahydrofuran (2.0 mL) was stirred at room temperature for 3 h. Aprecipitate had formed. The crude was carried forward. The mixture wascooled in an ice bath then hydrazine hydrate (78 μL, 1.612 mmol) wasadded. The reaction was allowed to warm to room temperature overnightthen concentrated. The crude was carried forward. ESI MS m/z 387 [M+H]⁺.

Step 2.

A mixture of crude tert-butyl3-(4-(hydrazinocarbonyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(208 mg, 0.538 mmol), triethyl orthoformate (2.7 mL, 16.21 mmol), andacetic acid (1.0 mL, 17.47 mmol) was stirred at 100° C. A yellowprecipitate formed. Upon completion, the reaction mixture was cooled toroom temperature, diluted with CH₂Cl₂ and the mixture sonicated. Theprecipitate was collected, washed with CH₂Cl₂, and dried in vacuo toprovide of(4-(1,3,4-oxadiazol-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (98 mg)as a yellow solid.

Example 39: Preparation of(1H-indol-3-yl)(4-(5-methyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methanone(ARI-060)

Step 1.

To a stirred suspension of2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (200 mg, 0.537 mmol) in dichloromethane (7.0 mL) at roomtemperature was added HATU (408 mg, 1.074 mmol) followed by DIPEA (0.141mL, 0.806 mmol). N,N-Dimethylformamide (0.7 mL) was added to aidsolubility. After 10 min, acetohydrazide (47.7 mg, 0.644 mmol) wasadded. Upon completion, the reaction mixture was absorbed on silica gel.Chromatography (silica gel, CH₂Cl₂ to 10% MeOH/CH₂Cl₂) gave tert-butyl3-(4-(2-acetylhydrazine-1-carbonyl)thiazole-2-carbonyl)-1H-indole-1-carboxylateas an off-white solid (347, mg). ESI MS m/z 427 [M−H]⁻.

Step 2.

To a stirred suspension of tert-butyl3-(4-(2-acetylhydrazine-1-carbonyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(230 mg, 0.537 mmol) in dichloromethane (20 mL) at room temperature wasadded triethylamine (0.374 mL, 2.68 mmol) followed by tosyl-chloride(307 mg, 1.610 mmol). The reaction mixture was heated to 65° C. withstirring for 3 h. A clear solution formed. The reaction mixture was thenabsorbed on silica gel. Chromatography (silica gel, heptane to 65%EtOAc/heptane) gave tert-butyl3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(172, mg) as an off-white solid. ESI MS m/z 411[M+H]⁺.

Step 3.

To a stirred suspension of tert-butyl3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(162 mg, 0.395 mmol) in methanol (8 mL) at room temperature was addedpotassium carbonate (164 mg, 1.184 mmol). Upon completion, the mixturewas cooled in an ice-water bath, and neutralized with 2 M HCl. Theprecipitate was collected by filtration, washed with water and methanol,and dried in vacuo to provide(1H-indol-3-yl)(4-(5-methyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)methanone(130 mg) as a yellow solid.

Example 40: Preparation of2-(1H-indole-3-carbonyl)thiazole-4-carbaldehyde (ARI-061)

Potassium carbonate (0.175 g, 1.263 mmol) and tert-butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (0.150 g, 0.421mmol) were suspended in methanol (4.21 ml). Upon completion, thereaction mixture was acidified with 1M HCl and extracted with EtOAc. Theorganic was then concentrated onto silica gel. Chromatography (silicagel, heptane to 50% EtOAc/heptane) gave2-(1H-indole-3-carbonyl)thiazole-4-carbaldehyde (0.090 g) as a yellowsolid.

Example 41: Preparation of(4-(1H-1,2,3-triazol-5-yl)thiazol-2-yl)(1H-indol-3-yl)methanone(ARI-062)

To a stirred solution of (4-ethynylthiazol-2-yl)(1H-indol-3-yl)methanone(150 mg, 0.595 mmol), and copper(I) iodide (5.66 mg, 0.030 mmol) inN,N-dimethylformamide (4.5 mL)/methanol (0.500 mL) was added TMSN₃(0.118 mL, 0.892 mmol). The reaction mixture was stirred in a sealedreaction vessel at 100° C. for 6 h. The reaction mixture wasconcentrated in vacuo. The residue was dissolved in hot MeOH/water,filtered and the filtrate concentrated to dryness. The resulting residuewas triturated with CH₂Cl₂ and dried in vacuo to provide(4-(1H-1,2,3-triazol-5-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (154 mg)as a yellow solid.

Example 42: Preparation of2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-aminoacetic Acid (ARI-063)

Step 1. To a solution of ammonium acetate (130 mg, 1.684 mmol), sodiumcyanide (30.3 mg, 0.617 mmol) and ammonium hydroxide (170 μL, 1.268mmol) in water (500 μL)/ethanol (500 μL) at room temperature was addedtert-butyl 3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (200mg, 0.561 mmol). The cloudy reaction mixture was stirred for 18.5 h.More ethanol (500 μL), ammonium acetate (130 mg, 1.684 mmol), ammoniumhydroxide (170 μL, 1.268 mmol), and sodium cyanide (30.3 mg, 0.617 mmol)were added. Stirring was continued for an additional 19.5 h. Moreethanol (500 μL), ammonium acetate (130 mg, 1.684 mmol), ammoniumhydroxide (170 μL, 1.268 mmol), and tetrabutylammonium cyanide (166 mg,0.617 mmol) were added. Stirring was continued for 24 h. The reactionmixture was diluted with EtOAc (3 mL), washed with water (1 mL), driedover Na₂SO₄, filtered, and concentrated. The residue was dried in vacuoto an orange-brown sticky solid (293 mg). The crude was carried forward.ESI MS m/z 383 [M+H]⁺.

Step 2.

To a stirred solution of crude tert-butyl3-(4-(amino(cyano)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(215 mg, 0.562 mmol) in acetic acid (4.0 mL) at room temperature wasadded concentrated hydrochloric acid (2.0 mL, 24.36 mmol). The reactionmixture was stirred at 100° C. for 17 h. The reaction mixture was cooledto room temperature and then concentrated to dryness. Chromatography(C18, H₂O to 50% MeCN/H₂O) gave2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-aminoacetic acid (26.1 mg) asa light red solid.

Example 43: Preparation of(1H-indol-3-yl)(4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)methanone(ARI-064)

Step 1.

To a stirred mixture of2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (240 mg, 0.644 mmol), ammonium chloride (241 mg, 4.51 mmol), HOBt(148 mg, 0.967 mmol) and EDC (371 mg, 1.933 mmol) were addedN,N-dimethylformamide (6.5 mL) and then DIPEA (0.675 mL, 3.87 mmol).Upon completion, the reaction mixture was diluted with water andsaturated NaHCO₃ (aq). The precipitate was collected by filtration,washed with water, and dried in vacuo to provide tert-butyl3-(4-carbamoylthiazole-2-carbonyl)-1H-indole-1-carboxylate (224 mg) as alight yellow solid. ESI MS m/z 372 [M+H]⁺.

Step 2.

To an ice-cold, stirred solution of tert-butyl3-(4-carbamoylthiazole-2-carbonyl)-1H-indole-1-carboxylate (200 mg,0.538 mmol) in methanol (10.0 mL) was added sodium borohydride (61.1 mg,1.615 mmol) in two portions. The reaction mixture was stirred at 0° C.for 1 h. Then, the reaction mixture was quenched with 2 M HCl until pHreached 5-6 and then concentrated to dryness. The residue waspartitioned between EtOAc and water. The organic was washed with brine,dried (Na₂SO₄), filtered, and concentrated to give tert-butyl3-((4-carbamoylthiazol-2-yl)(hydroxy)methyl)-1H-indole-1-carboxylate(224 mg) as a colorless syrup. The crude was carried forward. ESI MS m/z374 [M+H]⁺.

Step 3.

To a stirred solution of tert-butyl3-((4-carbamoylthiazol-2-yl)(hydroxy)methyl)-1H-indole-1-carboxylate(224 mg, 0.538 mmol) and dihydropyran (98 μL, 1.072 mmol) indichloromethane (5.5 mL) at room temperature was added pyridiniump-toluenesulfonate (6.76 mg, 0.027 mmol). The reaction mixture wasstirred for 20.5 h. The reaction mixture was absorbed on silica gel.Chromatography (silica gel, heptane to 70% EtOAc/heptane) gavetert-butyl3-((4-carbamoylthiazol-2-yl)((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-indole-1-carboxylate(244 mg) as a light yellow syrup. ESI MS m/z 458 [M+H]⁺.

Step 4.

A mixture of tert-butyl3-((4-carbamoylthiazol-2-yl)((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-indole-1-carboxylate(5 mg, 10.93 μmol) and 1,1-dimethoxy-N,N-dimethylethane-1-amine (150 μL,1.026 mmol) was stirred at 80° C. for 15 h. The reaction mixture wasconcentrated and residue dried in vacuo to provide tert-butyl(E)-3-((4-((1-(dimethylamino)ethylidene)carbamoyl)thiazol-2-yl)((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-indole-1-carboxylateas a brown viscous oil, which was used in the next step withoutpurification. ESI MS m/z 527 [M+H]⁺.

Step 5.

A solution of crude tert-butyl(E)-3-((4-((1-(dimethylamino)ethylidene)carbamoyl)thiazol-2-yl)((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-indole-1-carboxylate(261 mg, 0.496 mmol) and hydrazine hydrate (77 μL, 2.478 mmol) in aceticacid (3.5 mL) was stirred at 80° C. Upon completion, the reactionmixture was cooled to room temperature and absorbed onto silica gel.Chromatography (silica gel, CH₂Cl₂ to 50% 80:18:2CH₂Cl₂/MeOH/concentrated NH₄OH) gave tert-butyl3-(hydroxy(4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)methyl)-1H-indole-1-carboxylate(41 mg) as a yellow solid. ESI MS m/z 496 [M+H]⁺.

Step 6.

To a stirred solution of tert-butyl3-(hydroxy(4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)methyl)-1H-indole-1-carboxylate(41 mg, 0.100 mmol) in dichloromethane (2.5 mL) at room temperature wasadded Dess-Martin periodinane (54.9 mg, 0.130 mmol). Upon completion thereaction was quenched with saturated NaHCO₃ (2 mL) and 10% Na₂S₂O₃ (2mL). The organic layer was separated. The aqueous layer was extractedwith CH₂Cl₂ (2×). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated. Chromatography (silica gel, CH₂Cl₂ to 10%MeOH/CH₂Cl₂) gave tert-butyl3-(4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(29.1 mg) as a yellow solid. ESI MS m/z 410 [M+H]⁺.

Step 7.

To a stirred suspension of tert-butyl3-(4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(29 mg, 0.071 mmol) in methanol (2.4 mL) at room temperature was addedpotassium carbonate (29.4 mg, 0.212 mmol). Upon completion, the reactionmixture was neutralized with 2 M HCl while cooled in an ice-water bath.The resulting precipitate was collected, washed with water and dried invacuo to provide(1H-indol-3-yl)(4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)methanone(19.1 mg) as a light yellow solid.

Alternatively, ARI-064 was synthesized according to the scheme of FIG.18 and by the following method:

Step:(1H-indol-3-yl)(4-(5-methyl-4H-1,2,4-triazol-3-yl)thiazol-2-yl)methanone(ARI-064)

A suspension of compound 49-1 (1.45 g, 3.7 mmol), acetimidamidehydrochloride (700 mg, 7.5 mmol) and NaOH (300 mg, 7.5 mmol) in dioxane(20 mL) was stirred for 30 min at 110° C. under microwave. After cooledto room temperature, the mixture was filtered, and the solid wascollected, washed with EtOAc (20 mL×3) and MeOH (20 mL×3), dried toafford compound ARI-064 (880 mg, 76% yield) in the form of a yellowsolid. ¹H-NMR (400 MHz, DMSO-d6): δ 12.39 (bs, 1H), 9.38 (s, 1H), 8.51(s, 1H), 8.33˜8.36 (m, 1H), 7.28˜7.62 (d, J=6.4 Hz, 1H), 7.29˜7.32 (m,2H), 2.51 (s, 3H). LC-MS: m/z 308.1 [M−H]⁻.

Example 44: Preparation of(4-(1,2,4-oxadiazol-3-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (ARI-071)

Step 1.

A mixture of 2-(1H-indole-3-carbonyl)thiazole-4-carbonitrile (160 mg,0.632 mmol), K₃PO₄ (402 mg, 1.895 mmol) and hydroxylamine hydrochloride(110 mg, 1.579 mmol) in DMF (10 mL) was heated to 100° C. in a microwavereactor for 30 min. Triethyl orthoformate (3.16 mL, 18.97 mmol),pyridinium p-toluenesulfonate (PPTS) (31.8 mg, 0.126 mmol) and TFA(0.317 mL, 4.11 mmol) was added. The reaction mixture was further heatedto 100° C. on a microwave reactor for 2 h. The reaction mixture wasconcentrated in vacuo. The residue was triturated with water bysonication. The precipitate was collected, washed with water, dried.Chromatography (silica gel, CH₂Cl₂ to 6% MeOH/CH₂Cl₂) gave(4-(1,2,4-oxadiazol-3-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (69 mg)as a yellow solid.

Example 45: Preparation of (1H-indol-3-yl)(thiazol-4-yl)methanone(ARI-072)

Prepared according to the method described in Example 2 except thatethyl 4-(chlorocarbonyl)thiazole-2-carboxylate was used instead of4-bromothiazole-2-carbonyl chloride in Step 1 and the Boc deprotectionwas effected using NaOH in methanol.

Ethyl 4-(chlorocarbonyl)thiazole-2-carboxylate was obtained fromcommercial ethyl 4-(chlorocarbonyl)thiazole-2-carboxylate as follows. Toan ice-cold suspension of 2-(ethoxycarbonyl)thiazole-4-carboxylic acid(1 g, 4.97 mmol) in DCM (9.94 ml) was added 2 drops of DMF then oxalylchloride (0.505 ml, 5.96 mmol) was added dropwise. The bath was removedand a large bubbler was added. Upon nearing room temperature CO₂evolution was observed and after 3 h, gas evolution ceased. The solutionwas concentrated under reduced pressure and used as crude.

Example 46: Preparation of (1H-indol-3-yl)(phenyl)methanone (ARI-073)

Prepared according to the method described in Example 2 except thatbenzoyl chloride was used instead of 4-bromothiazole-2-carbonylchloride.

Example 47: Preparation of (1H-indol-3-yl)(m-tolyl)methanone (ARI-074)

Prepared according to the method described in Example 2 except that3-methylbenzoyl chloride was used instead of 4-bromothiazole-2-carbonylchloride.

Example 48: Preparation of2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-aminoacetonitrile (ARI-075)

Step 1.

A solution of ammonium acetate (195 mg, 2.53 mmol), tetrabutylammoniumcyanide (249 mg, 0.926 mmol), and ammonium hydroxide (0.255 mL, 1.902mmol) in water (1.2 mL) was added to a suspension of tert-butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (300 mg, 0.842mmol) in ethanol (1.2 mL) at room temperature. The cloudy reactionmixture was stirred for 26 h. The reaction mixture was diluted withEtOAc, washed with water, dried over Na₂SO₄, filtered, and concentrated.Chromatography (silica gel, CH₂Cl₂ to 4.5% MeOH/CH₂Cl₂) and then (C18,H₂O to CH₃CN)) gave2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-aminoacetonitrile (37.6 mg)as a yellow solid.

Alternatively, ARI-075 was synthesized according to the scheme of FIG.19 and by the following method:

Step 1: tert-Butyl3-(4-(amino(cyano)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(93-1)

Trimethylsilyl cyanide (0.74 mL, 5.5 mmol) was added to a solution ofcompound 1-4 (1.40 g, 4 mmol) in THF (5 mL) and NH₃-MeOH (7M solution,20 mL) at room temperature. The mixture was stirred for 2 h, thenconcentrated to dryness to afford compound 93-1 (2.0 g, ˜100% yield),which was used for next step without further purification.

Step 2: 2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-aminoacetonitrile(ARI-075)

The BOC group of compound 93-1 (2.00 g, 5 mmol) was removed as describedin Example 24 (treatment with K₂CO₃ in methanol held at 50° C.) to givetitle compound ARI-075 in the form of a yellow solid (680 mg, 43%yield). ¹H-NMR (400 MHz, DMSO-d6): δ 12.37 (bs, 1H), 9.17 (s, 1H),8.31˜8.35 (m, 1H), 8.07 (s, 1H), 7.56˜7.59 (d, J=6.0 Hz, 1H), 7.28˜7.33(m, 2H), 5.34˜5.39 (t, J=8.0 Hz, 1H), 3.05˜3.08 (d, J=8.0 Hz, 1H).LC-MS: m/z 281.0 [M−H]⁻.

Example 49: Preparation of (1H-indol-3-yl)(pyridin-2-yl)methanone(ARI-081)

Prepared according to the method described in Example 2 except thatpicolinoyl chloride hydrochloride was used instead of4-bromothiazole-2-carbonyl chloride.

Example 50: Preparation of methyl 3-(1H-indole-3-carbonyl)benzoate(ARI-082)

Prepared according to the method described in Example 2 except thatmethyl 3-(chlorocarbonyl)benzoate was used instead of4-bromothiazole-2-carbonyl chloride. The carboxylic acid was the primaryproduct which was subsequently esterified by treatment with sulfuricacid in methanol at 100° C.

Example 51: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone(ARI-083)

Step 1.

To a stirred suspension of tert-butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (150 mg, 0.421mmol) in methanol (0.90 mL)/N,N-dimethylformamide (0.900 mL) at roomtemperature was added a solution of hydrazinecarboxamide (46.9 mg, 0.421mmol) and sodium acetate (34.5 mg, 0.421 mmol) in water (0.900 mL). Thereaction mixture was stirred for 21.5 h. The reaction mixture wasconcentrated to dryness and the residue was dried in vacuo to providetert-butyl3-(4-((2-carbamoylhydrazono)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylateas a light yellow solid which was carried forward as crude. ESI MS m/z414 [M+H]⁺.

Step 2.

To a stirred cloudy solution of crude tert-butyl3-(4-((2-carbamoylhydrazono)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(174 mg, 0.421 mmol) in 1,4-dioxane (30 mL) at room temperature wasadded potassium carbonate (174 mg, 1.263 mmol) followed by iodine (128mg, 0.505 mmol). The reaction mixture was stirred at 80° C. for 25 h.The reaction mixture was cooled to room temperature and diluted withwater (30 mL). The resulting precipitate was collected, washed withwater, and dried in vacuo to provide tert-butyl3-(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(155 mg) as a yellow solid. ESI MS m/z 410 [M−H]⁻.

Step 3.

To a stirred suspension of tert-butyl3-(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(155 mg, 0.377 mmol) in methanol (12.5 mL) at room temperature was addedpotassium carbonate (156 mg, 1.130 mmol). The reaction mixture wasstirred for 15.5 h. The reaction mixture was cooled in an ice-water bathand neutralized with 2M HCl. The resulting precipitate was collected,washed with water, and dried in vacuo to provide(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone(87.5 mg) as a yellow solid.

Example 52: Preparation of(1H-indol-3-yl)(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazol-2-yl)methanone(ARI-088)

Step 1.

To a −35° C. solution of tert-butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (1.63 g, 4.57mmol) and tetrabutylammonium acetate (0.034 g, 0.114 mmol) in DCM (100ml) was added trimethyl(trifluoromethyl)silane (0.676 ml, 4.57 mmol)dropwise. The reaction was allowed to slowly warm to room temperature.Upon completion, saturated NaCl was added. The layers were separated andthe organic dried (Na₂SO₄), filtered and concentrated. Chromatography(silica gel, heptane to CH₂Cl₂) gave tert-butyl3-(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(1.67 g) as a colorless hard film. ESI MS m/z 427 [M+H]⁺.

Step 2.

To tert-butyl3-(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(2.145 g, 5.03 mmol) was added MeOH (10.06 ml) then 1 M NaOH (aq) (10.06ml, 10.06 mmol) was added and the mixture heated to 65° C. for 30 min.The solvent was concentrated and the residue partitioned between 1 N HCland EtOAc. The organic phase was separated, washed with water and thenbrine, dried (Na₂SO₄), filtered and concentrated onto silica gel.Chromatography (silica gel, heptane to 45% EtOAc/heptane) gave(1H-indol-3-yl)(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazol-2-yl)methanone(1.44, g) as a yellow solid.

Example 53: Preparation of1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2,2,2-trifluoroethan-1-one(ARI-089)

Step 1.

To tert-butyl3-(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(417 mg, 0.978 mmol) and1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (539 mg,1.271 mmol) was added CH₂Cl₂ (10 mL). After 1 hr, the reaction wasquenched by the addition of saturated NaHCO₃ and 10% Na₂S₂O₃. Afterstirring 20 min, CH₂Cl₂ was added. After separation, the organic phasewas washed with a second portion of bicarbonate, dried over Na₂SO₄,filtered and concentrated. Chromatography (silica gel, heptane to 25%EtOAc/heptane) gave tert-butyl3-(4-(2,2,2-trifluoro-1,1-dihydroxyethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(409.7 mg) as a yellow solid. The mass spectrum for the product showsthat the product may exist as the diol ESI MS m/z 443 [M+H+H₂O]⁺.

Step 2.

To a solution of tert-butyl3-(4-(2,2,2-trifluoro-1,1-dihydroxyethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(180 mg, 0.407 mmol) in THF (2 ml) was added 2 M NaOH (aq) (1.2 ml, 2.4mmol) and the mixture was heated to 40° C. Upon completion, the reactionwas neutralized with 1 N HCl (aq). Chromatography (C18, H₂O to CH₃CN,liquid load) gave1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2,2,2-trifluoroethan-1-one (80mg) as a yellow solid.

Example 54: Preparation of(4-(5-amino-1,3,4-thiadiazol-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone(ARI-090)

Prepared according to the method described in Example 51 except thathydrazinecarbothioamide was used instead of hydrazinecarboxamide.

Example 55: Preparation of 3-(1H-indole-3-carbonyl)benzonitrile(ARI-091)

Step 1.

Oxalyl chloride (0.119 ml, 1.357 mmol) was added dropwise to an ice-coldsuspension of 3-(1H-indole-3-carbonyl)benzoic acid (0.300 g, 1.131 mmol)in tetrahydrofuran (10 ml). The ice bath was removed and the reactionstirred at ambient temperature. One drop of DMF was added and gas inflowswitched from nitrogen inlet to a bubbler. After the bubbling of CO₂ceased, ammonium hydroxide (0.944 ml, 6.79 mmol) was added at 0° C. Uponcompletion, the reaction mixture was concentrated under reducedpressure, then triturated with water then dried to give3-(1H-indole-3-carbonyl)benzamide. The crude solid was used as is. ESIMS m/z 264 [M−H]⁻.

Step 2.

A solution of 3-(1H-indole-3-carbonyl)benzamide (0.267 g, 1.010 mmol)and triethylamine (0.704 ml, 5.05 mmol) in tetrahydrofuran (10.10 ml)was stirred in an ice bath for 10 minutes. Trifluoroacetic anhydride(0.357 ml, 2.53 mmol) was added dropwise. Upon completion, the reactionmixture was poured over ice and diluted with ethyl acetate. The organiclayer was washed with 2M Na₂CO₃ and brine, then dried over sodiumsulfate, filtered and concentrated onto silica gel. Chromatography(silica gel, heptane to 50% EtOAc/heptane) gave3-(1H-indole-3-carbonyl)benzonitrile (109.7 mg) as an off-white solid.

Example 56: Preparation of(5-chloro-1H-indol-3-yl)(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)methanone(ARI-096)

Prepared according to the method described in Example 22 except that2-(1-(tert-butoxycarbonyl)-5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxylicacid, derived from 5-chloro-1H-indole-3-carboxylic acid was used insteadof 2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid.

Example 57: Preparation of2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carbonitrile (ARI-099)

Step 1.

Oxalyl chloride (0.129 ml, 1.475 mmol) was added dropwise to an ice-coldsuspension of2-(1-(tert-butoxycarbonyl)-5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (0.500 g, 1.229 mmol) in tetrahydrofuran (24 ml). The ice bath wasremoved and the reaction stirred at ambient temperature. Uponcompletion, the reaction mixture was concentrated under reduced pressurethen resuspended in tetrahydrofuran (24 ml) and chilled in an ice bath.Ammonium hydroxide (1.026 ml, 7.37 mmol) was added at 0° C. Uponcompletion, the reaction mixture was concentrated under reducedpressure, then triturated with water and concentrated. The solid (0.357g, 0.880 mmol) was suspended in methanol (8.80 ml) and potassiumcarbonate (0.365 g, 2.64 mmol) was added. Upon completion, the reactionmixture was concentrated, then suspended in water and adjusted to pH 4with 1M HCl, the biphasic mixture was filtered and dried to give2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxamide (0.244 g, 0.798mmol) as a yellow solid. ESI MS m/z 306 [M+H]⁺.

Step 2.

Triethylamine (0.556 ml, 3.99 mmol) was added to an ice-cold suspensionof 2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxamide (0.244 g,0.798 mmol) in tetrahydrofuran (7.98 ml), then stirred for ten minutes.Trifluoroacetic anhydride (0.282 ml, 1.995 mmol) was added dropwise tothe reaction mixture. Upon completion, the reaction mixture was pouredover ice, then diluted with ethyl acetate. The biphasic mixture wasfiltered and washed with water to provide2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carbonitrile (0.192 g) as ayellow solid.

Example 58: Preparation of(4-(1-amino-2,2,2-trifluoroethyl)thiazol-2-yl)(1H-indol-3-yl)methanone(ARI-100)

Step 1.

To an ice-cold solution of tert-butyl3-(4-(2,2,2-trifluoro-1-hydroxyethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(0.305 g, 0.715 mmol) in CH₂Cl₂ (7153 μl) was added triethylamine (299μl, 2.146 mmol) then methanesulfonylchloride (83 μl, 1.073 mmol)dropwise. Upon completion, the cold reaction mixture was poured intosaturated NaHCO₃. The organic phase was separated and then dried(Na₂SO₄), filtered and concentrated to give tert-butyl3-(4-(2,2,2-trifluoro-1-((methylsulfonyl)oxy)ethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(422 mg) as a yellow gum. Used as is. ESI MS m/z 505 [M+H]⁺.

Step 2.

To a mixture of tert-butyl3-(4-(2,2,2-trifluoro-1-((methylsulfonyl)oxy)ethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(0.361 g, 0.715 mmol) and sodium azide (0.279 g, 4.29 mmol) was addedDMF. The reaction was heated to 60° C. and stirred overnight. PartialBoc removal was observed. Concentrated the DMF under vacuum. The residuewas partitioned between EtOAc and 5% aqueous LiCl. The organic phase waswashed with brine, dried (Na₂SO₄), filtered and concentrated to a yellowsolid (340 mg). The solid was treated with MeOH (20 mL) and 2 mL of 2NNaOH (aq). then heated the mixture to 50° C. Upon completion, themixture was neutralized with 1 N HCl then most of MeOH was evaporated.The mixture was then partitioned between EtOAc and H₂O. The organic wasdried over Na₂SO₄, and filtered to give(4-(1-azido-2,2,2-trifluoroethyl)thiazol-2-yl)(1H-indol-3-yl)methanone(245 mg) as a yellow solid which was used as is. ESI MS m/z 352 [M+H]⁺.

Step 3.

A stirred solution of crude(4-(1-azido-2,2,2-trifluoroethyl)thiazol-2-yl)(1H-indol-3-yl)methanone(242 mg, 0.689 mmol) in a mixture of THF (10 ml) and water (3.33 ml) washeated to 60° C. overnight. The mixture was absorbed onto a SCX-2 5 gcolumn. Eluted with 10% concentrated NH₄OH in MeOH and then furtherconcentrated. Chromatography (C18, H₂O to CH₃CN) gave(4-(1-amino-2,2,2-trifluoroethyl)thiazol-2-yl)(1H-indol-3-yl)methanone(90 mg) as a yellow solid.

Example 59: Preparation of(5-chloro-1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(ARI-109)

Step 1.

A mixture of tert-butyl5-chloro-3-(4-cyanothiazole-2-carbonyl)-1H-indole-1-carboxylate (0.860g, 2.217 mmol) and potassium carbonate (0.919 g, 6.65 mmol) were stirredin methanol (44.3 ml). Upon completion, the reaction mixture wasneutralized with 1M HCl, and extracted with ethyl acetate thenconcentrated onto silica gel. Chromatography (silica gel, heptane toEtOAc then 20% MeOH/DCM) gave methyl2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carbimidate (0.705 g). ESIMS m/z 320 [M+H]⁺.

Step 2.

Methyl 2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carbimidate (0.200 g,0.625 mmol), potassium phosphate (0.398 g, 1.876 mmol) and hydroxylaminehydrochloride (0.109 g, 1.564 mmol) in N,N-dimethylformamide (7.82 ml)were heated to 100° C. in the microwave for 30 minutes. Acetyl chloride(0.36 ml, 5.06 mmol) was added and the reaction mixture was resubjectedto heating to 100° C. in the microwave for 5 h. After this time, thereaction mixture was concentrated under reduced pressure and trituratedwith water and then with hot methanol to provide(5-chloro-1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(144 mg). ESI MS m/z 345 [M+H]⁺.

Step 3.

DMAP (0.017 g, 0.136 mmol) was added to a suspension of(5-chloro-1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(0.188 g, 0.545 mmol) and Boc₂O (0.165 ml, 0.709 mmol) in acetonitrile(5.45 ml) at ambient temperature. Upon completion, the reaction mixturewas concentrated under reduced pressure onto silica gel. Chromatography(silica gel, heptane to 50% EtOAc/heptane) followed by reverse phasechromatography (C18, 5% to 100% acetonitrile/water) gave tert-butyl5-chloro-3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(24 mg). ESI MS m/z 445 [M+H]⁺.

Step 4.

To a suspension of tert-butyl5-chloro-3-(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(0.024 g, 0.054 mmol) in methanol (0.539 ml) was added potassiumcarbonate (0.030 g, 0.216 mmol) and the mixture was stirred at ambienttemperature overnight. The reaction mixture was concentrated underreduced pressure, suspended in water and acidified with 1 M HCl. Thesolid was collected by filtration to afford(5-chloro-1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(11.7 mg) as an off-white solid.

Example 60: Preparation of(4-(5-amino-1,2,4-oxadiazol-3-yl)thiazol-2-yl)(1H-indol-3-yl)methanone(ARI-110)

Step 1.

A mixture of 2-(1H-indole-3-carbonyl)thiazole-4-carbonitrile (25 mg,0.099 mmol), phosphoric acid, potassium salt (62.9 mg, 0.296 mmol) andhydroxylamine hydrochloride (17.15 mg, 0.247 mmol) in DMF (1.1 mL) washeated to 100° C. in a microwave reactor for 30 min. The reactionmixture was concentrated to dryness. The residue was diluted with brineand EtOAc. The precipitate was collected by filtration, washed withwater (3×), and then dried in vacuo to provideN′-hydroxy-2-(1H-indole-3-carbonyl)thiazole-4-carboximidamide (23.4 mg)as a yellow solid. ESI MS m/z 287 [M+H]⁺.

Step 2.

A mixture ofN′-hydroxy-2-(1H-indole-3-carbonyl)thiazole-4-carboximidamide (23.4 mg,0.082 mmol) and 2,2,2-trichloroacetic anhydride (150 μL, 0.821 mmol) wasstirred at 150° C. (bath temperature) for 2 h. The reaction mixture wascooled to room temperature and diluted with water and EtOAc. Afterstirring for 30 min, the organic layer was separated, washed withsaturated NaHCO₃ and brine, dried (Na₂SO₄), filtered and concentrated.Chromatography (silica gel, heptane to 30% EtOAc) gave(1H-indol-3-yl)(4-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(19 mg). ESI MS m/z 413 [M−H]⁻.

Step 3.

Ammonia (7 N) in methanol (2.0 mL, 14.0 mmol) was added to(1H-indol-3-yl)(4-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(19 mg, 0.046 mmol) at room temperature. The reaction mixture wasstirred for 15 h then concentrated to dryness and the residue was driedin vacuo to provide(4-(5-amino-1,2,4-oxadiazol-3-yl)thiazol-2-yl)(1H-indol-3-yl)methanone(15.4 mg) as a yellow solid.

Example 61: Preparation of(5-chloro-1H-indol-3-yl)(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(ARI-116)

A mixture of 2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carbonitrile(0.250 g, 0.869 mmol), hydroxylamine hydrochloride (0.151 g, 2.172mmol), and potassium phosphate, tribasic (0.553 g, 2.61 mmol) inN,N-dimethylformamide (10.86 ml) were heated to 100° C. in the microwavefor 1 h. Trifluoroacetic anhydride (0.491 ml, 3.48 mmol) was then addedto the cooled solution and the reaction was again heated to 100° C. in amicrowave reactor for an additional hour. The reaction mixture wasconcentrated. Chromatography (C18, 0 to 100% ACN/water) gave and(5-chloro-1H-indol-3-yl)(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(41.9 mg) as a yellow solid.

Example 62: Preparation of(1H-indol-3-yl)(4-(5-(methylamino)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(ARI-117)

Methylamine (2.0 M in THF, 15 mL, 30.0 mmol) was added to(1H-indol-3-yl)(4-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(120 mg, 0.290 mmol) at 0° C. The reaction mixture was stirred for 22 hwith gradual warming to room temperature. The reaction mixture wasconcentrated to dryness and the residue was dried in vacuo to provide(1H-indol-3-yl)(4-(5-(methylamino)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(79 mg) as a yellow solid.

Example 63: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5,6-dichloro-1H-indol-3-yl)methanone(ARI-120)

Prepared according to the method described in Example 131 except that5,6-dichloro-1H-indole instead of 5,6-difluoro-1H-indole was used inStep 1.

Example 64: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5,6-dichloro-1H-indol-3-yl)methanone(ARI-121)

ARI-121 was synthesized according to the scheme of FIG. 20 and by thefollowing method:

Step 1: tert-Butyl5-chloro-3-(4-(N′-hydroxycarbamimidoyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(96-1)

This compound was synthesized according to the protocol described inExample 21 step 1 from compound 39-2 to give title compound 96-1 in theform of a yellow solid (2.10 g, 83% yield).

Step 2: tert-Butyl3-(4-(5-amino-1,2,4-oxadiazol-3-yl)thiazole-2-carbonyl)-5-chloro-1H-indole-1-carboxylate(96-2)

BrCN (1.0 g, 9 mmol) was added to a suspension of compound 96-1 (420 mg,1 mmol) in EtOH (200 mL) and H₂O (50 mL) at room temperature. Themixture was heated to 65° C. and stirred for 20 h. After cooled to roomtemperature, the mixture was filtered to collect the solid. The solidwas washed with EtOH (10 mL×3), dried to afford compound 96-2 (290 mg,65% yield) as yellow solid.

Step 3:(4-(5-amino-1,2,4-oxadiazol-3-yl)thiazol-2-yl)(5-chloro-1H-indol-3-yl)methanone(ARI-121)

This compound was synthesized according to the protocol described inExample 116 step 2 from compound 96-2 (380 mg, 0.85 mmol) to give titlecompound ARI-121 in the form of a yellow solid (228 mg, 78% yield).¹H-NMR (400 MHz, DMSO-d6): δ 12.53 (bs, 1H), 9.14˜9.16 (d, J=2.4 Hz,1H), 8.59 (s, 1H), 8.30 (s, 1H), 8.10 (s, 2H), 7.63˜7.66 (d, J=8.4 Hz,1H), 7.33˜7.36 (m, 1H). LC-MS: m/z 344.3 [M−H]⁻.

Example 65: Preparation of ethyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (PTC17341-17, ARI-041)

ARI-041 was synthesized according to the scheme of FIG. 21 and by thefollowing method:

Step: Ethyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate

K₂CO₃ (1.85 g, 13.4 mmol) was added to a solution of compound 1-5 (2.5g, 6.7 mmol) in DMF (30 mL) at room temperature. The mixture was stirredfor 5 min, then iodoethane (1.57 g, 10.1 mmol) was added. The resultingmixture was stirred for 2 h, then quenched with water (200 mL). Themixture was stirred for 0.5 h, then filtered to collect the solid. Thesolid was washed with water (30 mL×3) and EtOAc (30 mL×3), dried toafford ethyl ester (2.52 g, 94% yield) as off-white solid.

The above ethyl ester (2.50 g, 6.3 mmol) was dissolved in THF/DCM (10mL/10 mL) at 0° C., and the mixture was allowed to warm to roomtemperate and was then stirred for 2 h. The mixture was concentrated todryness. The residue was suspended in saturated aqueous NaHCO₃ (50 mL)and EtOAc (50 mL), stirred for 0.5 h, then filtered to collect thesolid. The solid was washed with water (30 mL×3) and EtOAc (30 mL×3),dried to afford ethyl 2-(1H-indole-3-carbonyl)thiazole-4-carboxylate(1.70 g, 91% yield) as yellow solid. ¹H-NMR (400 MHz, DMSO-d6): δ 12.38(s, 1H), 9.10 (s, 1H), 8.87 (s, 1H), 8.30˜8.35 (m, 1H), 7.55˜7.62 (m,1H), 7.2˜87.33 (m, 2H), 4.35˜4.44 (q, J=7.2 Hz, 2H), 1.34˜1.40 (t, J=7.2Hz, 3H). LC-MS: m/z 301.2 [M+H]⁺.

Example 66: Preparation of isopropyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-042)

Prepared according to the method described in Example 14 except thatisopropanol was used instead of 1,3-propanediol.

Example 67: Preparation of propyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-043)

Prepared according to the method described in Example 14 except thatpropanol was used instead of 1,3-propanediol.

Example 68: Preparation of2-(5-chloro-1H-indole-3-carbonyl)-N-methylthiazole-4-carboxamide(PTC17341-06) (ARI-049)

ARI-049 was synthesized according to the scheme of FIG. 22 and by thefollowing method:

Step: 2-(5-Chloro-1H-indole-3-carbonyl)-N-methylthiazole-4-carboxamide(PTC17341-06, ARI-049)

HATU (2.40 g, 6.4 mmol) and DIPEA (1.90 g, 14.7 mmol) were added to asuspension of compound 2-5 (2.00 g, 4.9 mmol) and methylaminehydrochloride (0.50 g, 7.4 mmol) in DMF (20 mL) at room temperature. Themixture was stirred overnight, then quenched with H₂O (100 mL). Themixture was stirred for 0.5 h, then filtered to collect the solid. Thesolid was washed with water (30 mL×3) and EtOAc (30 mL×3), dried toafford amide (1.20 g, 58% yield) as off-white solid.

The above amide (1.20 g, 2.8 mmol) was dissolved in THF/DCM (10 mL/10mL) at 0° C., then the mixture was allowed to warm to room temperate andstirred for 2 h. The mixture was concentrated to dryness. The residuewas suspended in saturated aqueous NaHCO₃ (50 mL) and EtOAc (50 mL),stirred for 0.5 h, then filtered to collect the solid. The solid waswashed with water (30 mL×3) and EtOAc (30 mL×3), dried to affordPTC17341-06 (ARI-049) (820 mg, 89% yield) as yellow solid. ¹H-NMR (400MHz, DMSO-d6): δ 12.52 (bs, 1H), 9.50 (s, 1H), 8.74 (bs, 1H), 8.62 (s,1H), 8.30˜8.31 (d, J=2.0 Hz, 1H), 7.58˜7.62 (d, J=8.8 Hz, 1H), 7.30˜7.35(m, 2H), 2.85˜2.90 (d, J=4.8 Hz, 3H). LC-MS: m/z 318.0 [M−H]⁻.

Example 69: Preparation of methyl2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-055)

Prepared according to the method described in Example 14 except that2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxylic acid and methanolwere used.

Example 70: Preparation of2-(5,6-dibromo-1H-indole-3-carbonyl)-N-methylthiazole-4-carboxamide(ARI-057)

BOC-protected ARI-004 (2.3 g) was dissolved in glacial acetic acid (25mL). Br₂ (3 eq) was added dropwise. The resulting mixture was stirred at20˜30° C. for 72 h. The acetic acid was removed under vacuum to affordthe crude product as a 3:1 mixture of 5,6 dibromo and monobromocarboxamido products. The crude product mixture was recrystallized fromhot glacial acetic acid to afford 2.3 gm of ARI-057 as an off-whitesolid.

Example 71: Preparation of2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxylic Acid(PTC17341-05, ARI-058)

ARI-058 was synthesized according to the scheme of FIG. 23 and by thefollowing method:

Step: 2-(5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxylic Acid(PTC17341-05, ARI-058)

A solution of compound 2-5 (1.5 g, 3.7 mmol) in DCM (10 mL) and TFA (10mL) was stirred at room temperature for 3 h. The mixture wasconcentrated to dryness. The residue was suspended in EtOAc (20 mL),alkalified by saturated aqueous NaHCO₃ to pH of 7˜8, then acidified byaqueous 1N HCl to pH of 3. The mixture was filtered to collect thesolid. The solid was washed with water (10 mL×3) and EtOAc (10 mL×3),dried to afford ARI-058 (HCl salt, 1.1 g, 87% yield) as yellow solid.¹H-NMR (400 MHz, DMSO-d6): δ 13.46 (bs, 1H), 12.76 (s, 1H), 9.17 (s,1H), 8.83 (s, 1H), 8.28˜8.29 (d, J=2.0 Hz, 1H), 7.63˜7.66 (d, J=8.4 Hz,1H), 7.3˜17.35 (m, 1H) LC-MS: m/z 305.0 [M−H]⁻.

Example 72: Preparation of tert-butyl2-(1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-059)

Prepared according to the method described in Example 14 except thattert-butanol was used instead of 1,3-propanediol.

Example 73: Preparation of2-(5-fluoro-1H-indole-3-carbonyl)-N-methylthiazole-4-carboxamide(ARI-065)

Prepared according to the method described in Example 24 except that5-fluoro-1H-indole-3-carboxylic acid and methylamine were used.

Example 74: Preparation of methyl2-(5-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-066)

Prepared according to the method described in Example 14 except thatmethanol was used instead of 1,3-propanediol.

Example 75: Preparation of1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)ethan-1-one (ARI-077)

ARI-077 was synthesized according to the scheme of FIG. 24 and by thefollowing method:

Step 1.

HATU (12.9 g, 34 mmol) and DIPEA (10.1 g, 78 mmol) were added to asuspension of2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylicacid (10.0 g, 26 mmol) and N,O-dimethylhydroxyamine hydrochloride (3.7g, 38 mmol) in DMF (50 mL) at room temperature. The mixture was stirredovernight, then quenched with H₂O (200 mL). The mixture was stirred for0.5 h, then filtered to collect the solid. The solid was washed withwater (50 mL×3) and EtOAc (50 mL×3), dried to afford tert-butyl3-(4-(methoxy(methyl)carbamoyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(9.1 g, 84% yield) as off-white solid.

Step 2.

NaBH₄ (0.54 g, 14 mmol) was added portionwise to a solution of compoundtert-butyl3-(4-(methoxy(methyl)carbamoyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(5.88 g, 14 mmol) in DCM (50 mL) and EtOH (50 mL) at 0° C. over 10 min.The resulting mixture was stirred for 0.5 h, then quenched with water(100 mL), extracted with DCM (100 mL×3). The combined organic phaseswere washed with brine (200 mL×2), dried, concentrated to afford alcohol(˜6.0 g) as an oil. The alcohol (6.0 g, 14 mmol) and triethanolamine(TEA) (2.2 g, 28 mmol) were dissolved in THF (60 mL), and cooled to 0°C., then TMSCl (2.2 g, 20 mmol) was added dropwise over 10 min. Theresulting mixture was stirred for 2 h, then quenched with water (100mL), extracted with EtOAc (50 mL×3). The combined organic phases werewashed with saturated aqueous NaHCO₃ (50 mL×2) and brine (200 mL×2),dried, concentrated to afford compound tert-butyl3-((4-(methoxy(methyl)carbamoyl)thiazol-2-yl) (trimethylsilyloxy)methyl)-1H-indole-1-carboxylate (6.9 g, ˜100% yield) as an oil,which was used for next step without further purification.

Step 3.

MeMgBr (2 M in Et₂O, 5 mL, 10 mmol) was added portionwise to a solutionof compound tert-butyl 3-((4-(methoxy(methyl)carbamoyl)thiazol-2-yl)(trimethyl silyloxy)methyl)-1H-indole-1-carboxylate (2.0 g, 4.1 mmol) inTHF (20 mL) at 0° C. over 10 min. The resulting mixture was stirred for0.5 h, then quenched with saturated aqueous NH₄Cl (50 mL), extractedwith EtOAc (50 mL×3). The combined organic phases were washed with brine(100 mL×2), dried, concentrated to afford ketone (˜1.8 g) as an oil.

The above ketone (1.8 g) was dissolved in THF (20 mL),tetrabutylammonium fluoride (TBAF) (1.1 g, 4 mmol) was added. Themixture was stirred for 2 h at room temperature, then quenched withwater (50 mL), extracted with EtOAc (50 mL×3). The combined organicphases were washed with brine (100 mL×2), dried, concentrated todryness. The residue was purified by silica gel chromatography(EtOAc/Hexane=1:3) to afford tert-butyl3-((4-acetylthiazole-2-yl)(hydroxy)methyl)-1H-indole-1-carboxylate (950mg, 62% yield).

Step 4.

Pyridinium chlorochromate (PCC) (0.8 g, 3.7 mmol) was added to asolution of compound tert-butyl3-((4-acetylthiazole-2-yl)(hydroxy)methyl)-1H-indole-1-carboxylate (950mg, 2.6 mmol) in DCM (50 mL) at room temperature. The resulting mixturewas stirred overnight, then quenched with water (50 mL). The mixture wasfiltered, and the filtrate was extracted with DCM (50 mL×3). Thecombined organic phases were washed with brine (100 mL×2), dried,concentrated to dryness. The residue was purified by silica gelchromatography (EtOAc/Hexane/THF=1:3:1) to afford tert-butyl3-(4-acetylthiazole-2-carbonyl)-1H-indole-1-carboxylate (670 mg, 69%yield).

Step 5.

A solution of tert-butyl3-(4-acetylthiazole-2-carbonyl)-1H-indole-1-carboxylate (1.5 g, 3.7mmol) in DCM (10 mL) and TFA (10 mL) was stirred at room temperature.Upon completion, the mixture was concentrated to dryness. The residuewas suspended in EtOAc basified with saturated aqueous NaHCO₃ to pH of7˜8, then acidified by aqueous 1N HCl to pH of 3. The mixture wasfiltered to collect the solid. The solid was washed with water andEtOAc, dried to afford1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)ethan-1-one in the form of ayellow solid (660 mg, 90% yield). ¹H-NMR (400 MHz, DMSO-d6): δ 12.35(bs, 1H), 9.18 (s, 1H), 8.86 (s, 1H), 8.32 (m, 1H), 7.59 (m, 1H), 7.31(m, 2H), 2.74 (s, 3H). LC-MS: m/z 270 [M+H]⁺.

Example 76: Preparation of1-(2-(5-chloro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-067)

Prepared according to the method described in Example 75 except that2-(1-(tert-butoxycarbonyl)-5-chloro-1H-indole-3-carbonyl)thiazole-4-carboxylicacid was used.

Example 77: Synthesis of(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl) methanone (PTC17341-16,ARI-068)

(S)-(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl) methanone(PTC17341-16A, ARI-092) and (R)-(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (PTC17341-16B, ARI-094)

ARI-068 was synthesized according to the scheme of FIG. 25 and by thefollowing method:

Step 1: tert-Butyl3-(4-(1-hydroxypropyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(78-1)

NaBH₄ (60 mg, 1.6 mmol, 0.6 eq) was added portionwise to a solution ofcompound Boc-ARI-002 (1.0 g, 2.6 mmol) in DCM (30 mL) and MeOH (20 mL)at 0° C. The mixture was stirred for 2 h, then quenched with H₂O (30mL), extracted with EtOAc (50 mL×3). The combined organic phases werewashed with brine (50 mL×3), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (hexane/EtOAc=2:1) to give compound 78-1 (700 mg, 70%yield) as an oil.

Step 2: (4-(1-Hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone(PTC17341-16)

This compound was synthesized according to the protocol described inExample 71 from compound 78-1 (2.2 g, 5.7 mmol) to give title compoundPTC17341-16 (ARI-068) in the form of a yellow solid (1.4 g, 86% yield).¹H-NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 9.15 (d, J=2.0 Hz, 1H),8.30˜8.34 (m, 1H), 7.82 (s, 1H), 7.55˜7.60 (m, 1H), 7.26˜7.30 (m, 2H),5.46˜5.48 (d, J=5.2 Hz, 1H), 4.71˜4.77 (m, 1H), 1.90˜2.00 (m, 1H),1.75˜1.88 (m, 1H), 0.90˜0.99 (t, J=5.4 Hz, 3H). LC-MS: m/z 287.2 [M+H]⁺.

Step 3: (S)-(4-(1-Hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone(PTC17341-16A) and (R)-(4-(1-Hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (PTC17341-16B)

Compound PTC17341-16 (1.0 g, 3.5 mmol) was separated by chiral prep-HPLCto afford compound PTC17341-16A (ARI-092) (140 mg, 14% yield) andPTC17341-16B (ARI-094) (128 mg, 13% yield).

PTC17341-16A (ARI-092): yellow solid, ¹H-NMR (400 MHz, DMSO-d6): δ 12.21(bs, 1H), 9.10 (s, 1H), 8.30˜8.34 (m, 1H), 7.82 (s, 1H), 7.55˜7.60 (m,1H), 7.24˜7.31 (m, 2H), 5.44˜5.47 (d, J=6.8 Hz, 1H), 4.70˜7.77 (m, 1H),1.88˜1.95 (m, 1H), 1.75˜1.85 (m, 1H), 0.90˜0.96 (t, J=6.0 Hz, 3H).LC-MS: m/z 287.2 [M+H]⁺.

PTC17341-16B (ARI-094): yellow solid, ¹H-NMR (400 MHz, DMSO-d6): δ 12.22(bs, 1H), 9.10 (s, 1H), 8.30˜8.34 (m, 1H), 7.82 (s, 1H), 7.55˜7.60 (m,1H), 7.24˜7.31 (m, 2H), 5.44˜5.47 (d, J=6.0 Hz, 1H), 4.70˜4.77 (m, 1H),1.88˜2.05 (m, 1H), 1.74˜1.85 (m, 1H), 0.92˜0.98 (t, J=6.0 Hz, 3H).LC-MS: m/z 287.2 [M+H]⁺.

Example 78: Synthesis of(E)-(1H-indol-3-yl)(4-(1-(methoxyimino)-2-methyl propyl)thiazol-2-yl)methanone (PTC17341-22-A) and(Z)-(1H-indol-3-yl)(4-(1-(methoxyimino)-2-methylpropyl)thiazol-2-yl)methanone(PTC17341-22-B) (ARI-069 and ARI-070)

ARI-069 and ARI-070 were synthesized according to the scheme of FIG. 26and by the following method:

Step 1: tert-Butyl3-((4-isobutyrylthiazol-2-yl)(trimethylsilyloxy)methyl)-1H-indole-1-carboxylate(80-1)

This compound was synthesized according to the protocol described inExample 127 from compound 40-2 (23.0 g, 47 mmol) to give title compound80-1 (15.3 g, 69% yield).

Step 2: (E)-tert-Butyl3-(hydroxy(4-(1-(methoxyimino)-2-methylpropyl)thiazol-2-yl)methyl)-1H-indole-1-carboxylate(80-2A) and (Z)-tert-butyl 3-(hydroxyl(4-(1-(methoxyimino)-2-methylpropyl)thiazol-2-yl)methyl)-1H-indole-1-carboxylate(80-2B)

NaOAc (2.64 g, 32 mmol) and methoxylamine hydrochloride (1.34 g, 16mmol) were added to a solution of compound 80-1 (3.80 g, 8 mmol) in EtOH(20 mL) and H₂O (50 mL) at room temperature. The mixture was heated to70° C. and stirred for 2 h. After cooling to room temperature, themixture was concentrated in vacuo. The residue was dissolved in THF (20mL), and TBAF (2.30 g, 8.8 mmol) was added. The mixture was stirred for2 h at room temperature, then quenched with water (50 mL), extractedwith EtOAc (50 mL×3). The combined organic phases were washed with brine(100 mL×2), dried, concentrated to dryness. The residue was purified bysilica gel chromatography (EtOAc/Hexane=1:15) and afforded compound80-2A (600 mg, 17% yield) and 80-2B (598 mg, 17% yield).

Step 3a: (E)-tert-Butyl3-(4-(1-(methoxyimino)-2-methylpropyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(80-3A)

This compound was synthesized according to the protocol described inExample 127 from compound 80-2A (600 mg, 1.4 mmol) to give titlecompound 80-3A (310 mg, 52% yield).

Step 3b: (Z)-tert-Butyl3-(4-(1-(methoxyimino)-2-methylpropyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(80-3B)

This compound was synthesized according to the protocol described inExample 127 from compound 80-2B (598 mg, 1.4 mmol) to give titlecompound 80-3B (301 mg, 50% yield).

Step 4a:(E)-(1H-indol-3-yl)(4-(1-(methoxyimino)-2-methylpropyl)thiazol-2-yl)methanone (PTC17341-22-A, ARI-069)

This compound was synthesized according to the protocol described inExample 71 from compound 80-3A (300 mg, 0.7 mmol) to give the titlecompound ARI-069 (PTC17341-22-A) in the form of a yellow solid (130 mg,57% yield). ¹H-NMR (400 MHz, DMSO-d6): δ 12.36 (bs, 1H), 9.09 (s, 1H),8.30˜8.34 (m, 1H), 8.21 (s, 1H), 7.55˜7.60 (m, 1H), 7.26˜7.30 (m, 2H),3.95 (s, 3H), 3.65˜3.69 (m, 1H), 1.24˜1.32 (m, 6H). LC-MS: m/z 328.3[M+H]⁺.

Step 4b:(Z)-(1H-indol-3-yl)(4-(1-(methoxyimino)-2-methylpropyl)thiazol-2-yl)methanone (PTC17341-22-B)

This compound was synthesized according to the protocol described inExample 71 from compound 80-3B (300 mg, 0.7 mmol) to give the titlecompound ARI-070 (PTC17341-22-B) in the form of a yellow solid (172 mg,75% yield). ¹H-NMR (400 MHz, DMSO-d6): δ 12.32 (bs, 1H), 9.02 (s, 1H),8.74 (s, 1H), 8.31˜8.33 (m, 1H), 7.56˜7.59 (m, 1H), 7.28˜7.31 (m, 2H),3.95 (s, 3H), 3.50˜3.55 (m, 1H), 1.24˜1.26 (d, J=6.8 Hz, 6H). LC-MS: m/z326.3 [M−H]⁻.

Example 79: Preparation of methyl2-(1H-indole-2-carbonyl)thiazole-4-carboxylate (ARI-076)

Prepared from indole 2-carboxylic acid by the method described inExample 130 to obtain 2-(1-(tert-butoxycarbonyl)-1H-indole-2-carbonyl)thiazole-4-carboxylic acid.2-(1-(tert-butoxycarbonyl)-1H-indole-2-carbonyl) thiazole-4-carboxylicacid was then transformed to methyl2-(1H-indole-2-carbonyl)thiazole-4-carboxylate (ARI-076) according tothe method described in Example 65 except that iodomethane instead ofiodoethane was used.

Example 80: Preparation of2-(5-methoxy-1H-indole-3-carbonyl)-N-methylthiazole-4-carboxamide(ARI-078)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using5-methoxy-1H-indole-3-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indole-3-carbonyl)thiazole-4-carboxylicacid which was transformed to the final product using the HATU and TFAmethods. See Example 27: Preparation ofN-(2-hydroxyethyl)-2-(1H-indole-3-carbonyl)thiazole-4-carboxamide(ARI-036).

Example 81: Preparation of2-(1H-indole-2-carbonyl)-N-methylthiazole-4-carboxamide (ARI-079)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using1H-indole-2-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-1H-indole-2-carbonyl)thiazole-4-carboxylicacid which was transformed to the methylamide using conditions describedin Example 24.

Example 82: Preparation of6-(1H-indole-3-carbonyl)pyrazine-2-carbonitrile (PTC17341-46, ARI-085)

ARI-085 was synthesized according to the scheme of FIG. 27 and by thefollowing method:

Step 1: tert-Butyl3-(6-bromopyrazine-2-carbonyl)-1H-indole-1-carboxylate (83-1)

A solution of compound 1-1 (2.00 g, 6.6 mmol) and 2,6-dibromopyrazine(5.50 g, 23 mmol) in THF (100 mL) was cooled to −78° C., and n-BuLi (1.6M solution in hexane, 8.4 mL, 13.4 mmol) was added dropwise at −78° C.over 10 min. The mixture was stirred for 0.5 h at this temperature, thenallowed to warm to 0° C. and quenched with aqueous 10% NH₄Cl (100 mL)and EtOAc (100 mL). The organic phase was collected and washed withwater (100 mL×2), saturated aqueous NaHCO₃ (100 mL×2), and brine (100mL×1), dried (Na₂SO₄), filtered and concentrated to dryness. The residuewas purified by silica gel chromatography (EtOAc/Hexane=1:5) andafforded compound 83-1 (2.10 g, 79% yield).

Step 2: 6-(1H-indole-3-carbonyl)pyrazine-2-carbonitrile (PTC17341-46,ARI-085)

This compound was synthesized according to the protocol described inExample 118 from compound 83-1 (1.00 g, 2.5 mmol) to give title compoundPTC17341-46 (ARI-085) in the form of a yellow solid (101 mg, 16% yield).¹H-NMR (400 MHz, DMSO-d6): δ 12.30 (bs, 1H), 9.4˜09.44 (m, 2H), 8.59 (s,1H), 8.32˜8.35 (m, 1H), 7.56˜7.60 (m, 1H), 7.29˜7.32 (m, 2H). LC-MS: m/z248.8 [M+H]⁺.

Example 83: Synthesis of methyl6-(1H-indole-3-carbonyl)pyrimidine-4-carboxylate (PTC17341-35) (ARI-086)

ARI-086 was synthesized according to the scheme of FIG. 28 and by thefollowing method:

Step 1: Dimethyl pyrimidine-4,6-dicarboxylate (81-1)

SOCl₂ (4.76 g, 4 mmol) was added to a solution ofpyrimidine-4,6-dicarboxylic acid (3.40 g, 2 mmol) in MeOH (250 mL) at 0°C. The mixture was heated under reflux and stirred for 5 h. Aftercooling to room temperature, the mixture was concentrated in vacuo. Theresidue was diluted with saturated aqueous NaHCO₃ (100 mL), andextracted with EtOAc (100 mL×3). The combined organic phases were washedwith brine (100 mL×2), dried, concentrated to dryness. The residue waspurified by silica gel chromatography (EtOAc/Hexane=1:5) and affordedcompound 81-1 (3.10 g, 79% yield).

Step 2: 6-(Methoxycarbonyl)pyrimidine-4-carboxylic Acid (81-2)

Sodium hydroxide (632 mg, 15.8 mmol) was added to a solution of compound81-1 (3.10 g, 15.8 mmol) in MeOH (60 mL) and H₂O (6 mL) at 0° C. Theresulting mixture was stirred for 2 h at room temperature, thenacidified with 1M HCl aqueous to pH of 3. The mixture was concentratedto dryness. The residue was azeotroped two times with THF (50 mLportions) to afford crude compound 81-2 (3.30 g, ˜100% yield), which wasused for next step without further purification.

Step 3: Methyl 6-(chlorocarbonyl)pyrimidine-4-carboxylate (81-3)

This compound was synthesized according to the protocol described inExample 84 from compound 81-2 (3.00 g, 16.5 mmol) to give title compound81-3 (3.25 g, ˜100% yield), which was used for next step without furtherpurification.

Step 4: Methyl 6-(1H-indole-3-carbonyl)pyrimidine-4-carboxylate(PTC17341-35, ARI-086)

This compound was synthesized according to the protocol described inExample 84 from compound 81-3 (3.25 g, 16.5 mmol) to give title compoundPTC17341-35 (ARI-086) in the form of a yellow solid (275 mg, 6% yield).¹H-NMR (400 MHz, DMSO-d6): δ 12.34 (bs, 1H), 9.58˜9.59 (d, J=1.6 Hz,1H), 8.80 (s, 1H), 8.41 (s, 1H), 8.33˜8.35 (m, 1H), 7.55˜7.58 (m, 1H),7.28˜7.32 (m, 2H), 3.97 (s, 3H). LC-MS: m/z 280.2 [M+H]⁺.

Example 84: Preparation of1-(2-(5-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-087)

ARI-087 was synthesized according to the scheme of FIG. 29 and by thefollowing method:

Step 1: 2-(Ethoxycarbonyl)thiazole-4-carboxylic Acid (70-1)

Ethyl thiooxamate (1.0 Kg, 7.52 mol) was added portion-wise to asolution of 2-bromopyruvic acid (1.38 Kg, 8.27 mol) in THF (4 L) over 20min while the reaction was cooled with water bath. The reaction mixturewas stirred for 12 h at room temperature. The reaction mixture wasfiltered to remove solid. The filtrate was concentrated to dryness toafford crude compound 70-1 (1.8 kg). The crude 70-1 was triturated withEtOAc/hexane/H₂O (1:3:2, 6 L), filtered, and the solid was furthertriturated with EtOAc/hexane (1:8, 3 L), filtered, and the solid wasdissolved in DCM (6 L), dried over anhydrous Na₂SO₄, concentrated toafford compound 70-1 (617 g, 41% yield based on ethyl thiooxamate) aslight yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.79 (s, 1H), 4.38˜4.46(q, J=7.2 Hz, 2H), 1.3˜1.38 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 4-(chlorocarbonyl)thiazole-2-carboxylate (70-2)

Oxalyl chloride (63.1 g, 0.497 mol) was added dropwise to a suspensionof compound 70-2 (50.0 g, 0.248 mol) in DCM (500 mL) at room temperatureover 0.5 h. The reaction mixture was stirred for 4 h, then concentrated.The residue was azeotroped two times with DCM (500 mL portions) toafford crude compound 70-2 (55.1 g, ˜100% yield), which was used fornext step without further purification.

Step 3: Ethyl 4-propionylthiazole-2-carboxylate (70-3)

A mixture of compound 70-2 (55.1 g, 0.248 mol) and copper(I) iodide (9.5g, 50 mmol) was stirred and cooled to −60° C. under N₂. EtMgBr (2M inTHF, 150 mL) was added dropwise at −60˜−45° C. over 1 h. The mixture wasstirred for 2 h at this temperature, and then quenched with saturatedNH₄Cl aqueous (500 mL). The mixture was warmed to room temperature, thenextracted with EtOAc (500 mL×3). The combined organic phases were washedwith brine (500 mL×2), dried, concentrated to dryness. The residue waspurified by silica gel column chromatography (hexane/EtOAc=20:1) to givecompound 70-3 (23.7 g, 45% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.83 (s, 1H), 4.39˜4.46 (q, J=7.2 Hz, 2H), 3.07˜3.14 (q,J=7.2 Hz, 2H), 1.33˜1.38 (t, J=7.2 Hz, 3H), 1.07˜1.11 (t, J=7.2 Hz, 3H).

Step 4: 4-Propionylthiazole-2-carboxylic Acid (70-4)

Lithium hydroxide monohydrate (3.8 g, 90 mmol) was added to a solutionof compound 70-3 (6.4 g, 30 mmol) in THF (60 mL) and H₂O (6 mL) at 0° C.The resulting mixture was stirred for 2 h at room temperature, thenacidified with 1M HCl aqueous to pH of 3. The mixture was concentratedto dryness. The residue was azeotroped two times with THF (50 mLportions) to afford crude compound 70-4 (10.9 g, ˜100% yield), which wasused for next step without further purification.

Step 5: 4-Propionylthiazole-2-carbonyl Chloride (70-5)

Oxalyl chloride (961 mg, 7.6 mol) was added dropwise to a suspension ofcompound 70-4 (700 mg, 3.8 mmol) in DCM (20 mL) at room temperature. Thereaction mixture was stirred for 4 h, then concentrated. The residue wasazeotroped two times with DCM (20 mL portions) to afford crude compound70-5 (750 mg, ˜100% yield), which was used for next step without furtherpurification.

Step 6: 1-(2-(5-Fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one(ARI-087)

MeMgBr (3M in THF, 1.5 mL, 4.4 mmol) was added dropwise to a mixture of7-fluoroindole (500 mg, 3.7 mmol) and anhydrous zinc chloride (1.5 g, 11mmol) in DCM (20 mL) at 0° C. under N₂. The mixture was stirred for 1 hat this temperature, and then a solution of compound 70-5 (750 mg, 3.7mmol) in THF (20 mL) was added at 0° C. The reaction mixture was allowedto warm to room temperature and stirred overnight. The mixture wasquenched with saturated aqueous NH₄Cl (100 mL), stirred for 20 min,filtered. The solid was collected, washed with water (30 mL×3), EtOAc(30 mL×3) and MeOH (30 mL×3), dried to afford ARI-087 (620 mg, 55% yieldfrom compound 70-3) as yellow solid. ¹H-NMR (400 MHz, DMSO-d6): δ 12.42(bs, 1H), 9.20 (s, 1H), 8.86 (s, 1H), 7.97˜8.00 (m, 1H), 7.60˜7.63 (m,1H), 7.16˜7.19 (m, 1H), 3.22˜3.26 (q, J=7.2 Hz, 2H), 1.13˜1.18 (t, J=7.2Hz, 3H). LC-MS: m/z 302.7 [M+H]⁺.

Example 85: Preparation of5-(1H-indole-3-carbonyl)pyrazine-2-carbonitrile (ARI-093)

Prepared from 2,5-dibromopyrazine according to the method described inExample 82.

Example 86: Preparation of methyl5-(1H-indole-3-carbonyl)pyrazine-2-carboxylate (ARI-095)

Prepared according to the method described in Example 83, except that3,6-carboxymethylpyrazine was used as the staring material.

Example 87: Preparation of1-(2-(5,6-dibromo-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one(ARI-097)

Starting with methyl 2-(5,6-dibromo-1H-indole-3-carbonyl)thiazole-4-carboxylate (PTC17341-11A) (prepared as shown below and asshown in the scheme of FIG. 30) according to the method described inExample 75 except that ethylmagnesium bromide was used instead ofmethylmagnesium bromide.

Step 1: Methyl2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylate(86-1)

This compound was synthesized according to the protocol described inExample 65 from compound 1-5 (10.00 g, 27 mmol) with MeI to give titlecompound 86-1 in the form of a yellow solid (9.8 g, 94% yield).

Step 2: Methyl2-(5,6-dibromo-1H-indole-3-carbonyl)thiazole-4-carboxylate(PTC17341-11A)

Compound 86-1 (3.0 g, 7.8 mmol) was dissolved in HOAc (25 mL), thenbromine (5.0 g, 31 mmol) was added at room temperature. The mixture wasstirred at 50° C. for 72 h. After cooled to room temperature, themixture was filtered, and the solid was collected, washed by HOAc (10mL×2) to afford crude PTC17341-11A. The crude was recrystallized withDMF/H2O (2:1, 50 mL) to give compound PTC17341-11A (2.3 g, 67% yield).¹H-NMR (400 MHz, DMSO-d6): δ 12.49 (bs, 1H), 9.07 (s, 1H), 8.90 (s, 1H),8.57 (s, 1H), 8.00 (s, 1H), 3.93 (s, 3H). LC-MS: m/z 422.6 [M+H]⁺.

Example 88: Preparation of methyl2-(7-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-101)

Starting from 7-fluoroindole-3-carboxylic acid, ARI-101 was prepared asdescribed in Example 130 to obtain2-(1-(tert-butoxycarbonyl)-7-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylate,which was then transformed to ARI-101 in the presence of K₂CO₃, MeI, andTFA by a method described in Example 65.

Example 89: Preparation of methyl2-(7-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-102)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using7-fluoro-1H-indole-3-carboxylic acid.

Example 90: Preparation of2-(5-chloro-1H-indole-2-carbonyl)-N-methylthiazole-4-carboxamide(ARI-103)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using5-chloro-1H-indole-2-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-5-chloro-1H-indole-2-carbonyl)thiazole-4-carboxylicacid which was transformed to the final product using conditionsdescribed in Example 24 or the HATU and TFA method described in Example68.

Example 91: Preparation of2-(7-fluoro-1H-indole-3-carbonyl)thiazole-4-carbonitrile (ARI-104)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using7-fluoro-1H-indole-3-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-7-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylicacid which was transformed to the final product using the methoddescribed in Example 57.

Example 92: Preparation of2-(5-fluoro-1H-indole-2-carbonyl)thiazole-4-carboxylic Acid (ARI-105)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid described in Example130 using 5-fluoro-1H-indole-2-carboxylic acid.

Example 93: Preparation of2-(5-chloro-1H-indole-2-carbonyl)thiazole-4-carboxylic Acid (ARI-106)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid (Example 130) using5-chloro-1H-indole-2-carboxylic acid.

Example 94: Preparation of2-(5-fluoro-1H-indole-2-carbonyl)thiazole-4-carbonitrile (ARI-107)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using5-fluoro-1H-indole-2-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-7-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylicacid which was transformed to the final product using the methoddescribed in Example 57.

Example 95: Preparation of2-(5-fluoro-1H-indole-2-carbonyl)-N-methylthiazole-4-carboxamide(ARI-108)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using5-fluoro-1H-indole-2-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-7-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylicacid which was transformed to the final product using methods describedin Examples 24 or the HATU and TFA method described in Example 68.

Example 96: Preparation of methyl2-(6-cyano-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-111)

Prepared according to the method described in Example 118 except that6-bromoindole-3-carboxylic acid instead of 5-bromoindole 3-carboxylicacid was used.

Example 97: Preparation of2-(5-fluoro-1H-indole-3-carbonyl)thiazole-4-carbonitrile (ARI-112)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using5-fluoro-1H-indole-2-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-7-fluoro-1H-indole-3-carbonyl)thiazole-4-carboxylicacid which was transformed to the final 4-cyanothiazole product by thepreviously described trifluoroacetic anhydride (TFAA)-mediateddehydration of the primary amide (see method described in Example 57).

Example 98: Preparation of2-(5-chloro-1H-indole-2-carbonyl)thiazole-4-carbonitrile (ARI-113)

Prepared according to the method for preparing the key intermediate2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid using5-chloro-1H-indole-2-carboxylic acid to obtain2-(1-(tert-butoxycarbonyl)-5-chloro-1H-indole-2-carbonyl)thiazole-4-carboxylicacid which was transformed to the final 4-cyanothiazole product by thepreviously described trifluoroacetic anhydride (TFAA)-mediateddehydration of the primary amide (see method described in Example 57).

Example 99: Preparation of(7-fluoro-1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(ARI-114)

Prepared from2-(1-(tert-butoxycarbonyl)-7-fluoro-1H-indole-2-carbonyl)thiazole-4-carboxylicacid (itself prepared from 7-fluoroindole-3-carboxylic acid by themethods described in Example 130) by the method described in Example 59.

Example 100: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(7-fluoro-1H-indol-3-yl)methanone(ARI-118)

Prepared according to the method described in Example 131 except that7-fluoroindole was used instead of 5,6-difluoroindole.

Example 101: Preparation of(5-fluoro-1H-indol-3-yl)(4-(5-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(ARI-119)

Prepared from 2-(1H-indole-5-fluoro-3-carbonyl)thiazole-4-carbonitrileaccording to the method described in Example 21.

Example 102: Preparation of(7-fluoro-1H-indol-3-yl)(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)methanone(PTC17341-95, ARI-123)

ARI-123 was synthesized according to the scheme of FIG. 31 and by thefollowing method:

Step 1: tert-Butyl3-(4-((1-aminoethylideneaminooxy)carbonyl)thiazole-2-carbonyl)-7-fluoro-1H-indole-1-carboxylate(56-1)

Oxalyl chloride (500 mg, 4 mmol) was added to a suspension of compound5-5 (780 mg, 2 mmol) in DCM (20 mL) at 0° C. The mixture was allowed towarm to room temperature and stirred 5 h. The mixture was concentratedto dryness. The residue was dissolved in DCM (5 mL) and added dropwiseto a suspension of N-hydroxyacetimidamide (220 mg, 3 mmol) and TEA (410mg, 4 mmol) in DCM (20 mL) at 0° C. over 10 min. The resulting mixturewas allowed to warm to room temperature and stirred 1 h. The mixture wasconcentrated to dryness. And the residue was purified by silica gelchromatography (EtOAc/Hexane/DCM=2:1:1) and afforded compound 56-1 (450mg, 50% yield).

Step 2: tert-Butyl7-fluoro-3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(56-2)

A solution of compound 56-1 (450 mg, 1 mmol) and TBAF (780 mg, 3 mmol)in THF (20 mL) was heated under reflux for 4 h. The mixture was cooledto room temperature, Boc₂O (430 mg, 2 mmol) and 4-dimethylaminopyridine(DMAP) (10 mg, cat.) were added to. The mixture was stirred for 2 h atroom temperature, then concentrated to dryness. The residue was purifiedby silica gel chromatography (EtOAc/Hexane/DCM=1:2:1) and affordedcompound 56-2 (150 mg, 35% yield).

Step 3: (7-fluoro-1H-indol-3-yl)(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)methanone (PTC17341-95, ARI-123)

This compound was synthesized according to the protocol described inExample 71 from compound 56-2 (150 mg, 0.35 mmol) to give title compoundPTC17341-95 (ARI-123) in the form of a yellow solid (85% yield). ¹H-NMR(400 MHz, DMSO-d6): δ 13.01 (bs, 1H), 9.12˜9.15 (d, J=8.0 Hz, 1H),8.12˜8.15 (d, J=8.0 Hz, 1H), 7.27˜7.33 (m, 1H), 7.17˜7.23 (m, 1H), 2.51(s, 3H). LC-MS: m/z 327.2 [M−H]⁻.

Example 103: Preparation of methyl 2-(7-cyano-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-124)

Prepared according to the method described in Example 118 except that7-bromoindole-3-carboxylic acids was used.

Example 104: Preparation of4-(1H-indole-3-carbonyl)pyrimidine-2-carbonitrile (ARI-125)

Prepared from 2,4-dibromopyrimidine as described in Example 82.

Example 105: Preparation of(5-fluoro-1H-indol-2-yl)(4-(3-methyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl)methanone(ARI-126)

Prepared from 2-(1H-indole-2-carbonyl)thiazole-4-carbonitrile accordingto the method described in Examples 21.

Example 106: Preparation of(1H-indol-3-yl)(5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)methanone(PTC17341-54, ARI-127)

ARI-127 was synthesized according to the scheme of FIG. 32 and by thefollowing method:

Step 1:5-(1-(tert-Butoxycarbonyl)-1H-indole-3-carbonyl)pyrazine-2-carboxylicAcid (99-1)

Lithium hydroxide monohydrate (380 mg, 9 mmol) was added to a solutionof compound PTC17341-39 (840 mg, 3 mmol) in THF (10 mL) and H₂O (10 mL)at 0° C. The resulting mixture was stirred for 2 h at room temperature,then acidified with 1M HCl aqueous to pH of 3. The mixture wasconcentrated to dryness. The residue was azeotroped two times with THF(50 mL portions), then dissolved in DMF (10 mL). DMAP (730 mg, 6 mmol)and Boc₂O (1.3 g, 6 mmol) were added to. The resulting mixture wasstirred overnight. The mixture was diluted with water (50 mL), acidifiedwith 1M HCl aqueous to pH of 3, extracted with EtOAc (50 mL×3). Thecombined organic phases were washed with water (50 mL×2), and brine (50mL×1), dried (Na₂SO₄), filtered and concentrated to dryness. The residuewas triturated with EtOAc/hexane (1:5, 50 mL), filtered and dried toafford compound 99-1 (810 mg, 73% yield).

Step 2: tert-Butyl3-(5-((1-aminoethylideneaminooxy)carbonyl)pyrazine-2-carbonyl)-1H-indole-1-carboxylate(99-2)

This compound was synthesized according to the protocol described inExample 102 step 1 from compound 99-1 (800 mg, 2.2 mmol) to give titlecompound 99-2 (1.10 g, ˜100% yield).

Steps 3/4:(1H-Indol-3-yl)(5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrazin-2-yl) methanone(PTC17341-54, ARI-127)

This compound was synthesized according to the protocol described inExample 102 step 2 and 3 from compound 99-2 (1.10 g, 2.2 mmol) to givetitle compound PTC17341-54 (ARI-127) in the form of a yellow solid (80mg, 12% yield for two steps). ¹H-NMR (400 MHz, DMSO-d6): δ 12.35 (bs,1H), 8.73˜8.72 (d, J=3.2 Hz, 1H), 8.37˜8.40 (d, m, 1H), 7.56˜7.60 (m,1H), 7.29˜7.33 (m, 2H), 2.53 (s, 3H). LC-MS: m/z 303.6 [M−H]⁻.

Example 107: Preparation of2-(5-chloro-2-methyl-1H-indole-3-carbonyl)thiazole-4-carboxylic Acid(ARI-128)

Starting with 2-methyl-indole-3-carboxylic acid, prepared as describedin Example 130.

Example 108: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5-fluoro-1H-indol-2-yl)methanone(ARI-129)

Prepared from 2-(1H-5-fluoro-indole-2-carbonyl)thiazole-4-carboxylicacid according to the method described in Example 131.

Example 109: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5-fluoro-1H-indol-2-yl)methanone(ARI-131)

Prepared from 2-(1H-5-chloro-indole-3-carbonyl)thiazole-4-carboxylicacid according to the method described in Example 131.

Example 110: Preparation of2-(5-fluoro-2-methyl-1H-indole-3-carbonyl)thiazole-4-carboxylic Acid(ARI-130)

Prepared from 2-methyl-5-fluoroindole-3-carboxylic acid according to themethod described in Example 130.

Example 111: Preparation of(5-fluoro-1H-indol-3-yl)(4-(3-methyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl)methanone(ARI-132)

Prepared from 2-(1H-5-fluoro-indole-3-carbonyl)thiazole-4-carboxylicacid according to the method described in Example 22.

Example 112: Preparation of(4-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)(5-chloro-1H-indol-3-yl)methanone(ARI-133)

Starting from 2-(1H-indole-5-chloro-3-carbonyl)thiazole-4-hydroxyamidate(prepared as described in Example 21), this compound was prepared asdescribed in Example 115.

Example 113: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5-chloro-2-methyl-1H-indol-3-yl)methanone(ARI-134)

Prepared from2-(1H-indole-2-methyl-5-chloro-3-carbonyl)thiazole-4-carboxylateaccording to the method described in Example 131.

Example 114. Preparation of(4-(5-(aminomethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl) (1H-indol-3-yl)methanone (PTC17341-108, ARI-137)

ARI-137 was synthesized according to the scheme of FIG. 33 and by thefollowing method:

Step 1: tert-Butyl 3-(4-(2-(2-(tert-butoxycarbonylamino)acetyl)hydrazinecarbonyl) thiazole-2-carbonyl)-1H-indole-1-carboxylate (59-1)

HATU (664 mg, 17. mmol) and DIPEA (520 mg, 4 mmol) were added to asolution of compound 1-5 (500 mg, 1.3 mmol) and Boc-glycine hydrazide(305 mg, 1.6 mmol) in DMF (10 mL) at room temperature. The mixture wasstirred overnight, then quenched with H₂O (50 mL). The mixture wasstirred for 0.5 h, then filtered to collect the solid. The solid waswashed with water (10 mL×3) and EtOAc (10 mL×3), dried to afford 59-1(700 mg, ˜100% yield) as off-white solid.

Step 2: tert-Butyl3-(4-(5-((tert-butoxycarbonylamino)methyl)-1,3,4-oxadiazol-2-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate (59-2)

Triphenylphosphine (470 mg, 1.8 mmol) and TEA (209 mg, 2.1 mmol) wereadded to a solution of compound 59-1 (700 mg, 1.3 mmol) in ACN (20 mL)at room temperature. The mixture was stirred for 20 min, then was addedCCl₄ (320 mg, 2.1 mmol). The mixture was heated to 50° C. and stirredfor 5 h. The mixture was cooled to room temperature, then concentrated.The residue was purified by silica gel chromatography(EtOAc/Hexane/DCM=1:1:1) and afforded compound 59-2 (290 mg, 42% yield).

Step 3:(4-(5-(Aminomethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (PTC17341-108, ARI-137)

This compound was synthesized according to the protocol described inExample 71 from compound 59-2 (290 mg, 0.55 mmol) to give title compoundPTC17341-108 (ARI-137) in the form of a yellow solid (80% yield). ¹H-NMR(400 MHz, DMSO-d6): δ 12.42 (bs, 1H), 9.14 (s, 1H), 8.90 (s, 1H),8.32˜8.35 (m, 1H), 7.60˜7.63 (m, 1H), 7.29˜7.34 (m, 2H), 4.04 (s, 2H),1.99 (s, 2H). LC-MS: m/z 326.4 [M+H]⁺.

Example 115: Preparation of(4-(5-(Aminomethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl) (1H-indol-3-yl)methanone (PTC17341-107, ARI-138)

ARI-138 was synthesized according to the scheme of FIG. 34 and by thefollowing method:

Step 1: tert-Butyl3-(4-(N-(2-(tert-butoxycarbonylamino)acetoxy)carbamimidoyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate (61-1)

T3P (50% solution in EtOAc, 1.5 g, 5 mmol) and TEA (606 mg, 6 mmol) wereadded to a solution of compound 45-1 (770 mg, 2 mmol) and Boc-glycine(350 mg, 2 mmol) in EtOAc (150 mL) at room temperature. The mixture washeated under reflux for 8 h. The mixture was cooled to room temperature,washed with brine (100 mL×3), dried, concentrated to afford compound61-1 (˜1 g), which was used for next step without further purification.

Step 2: tert-Butyl(3-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-1,2,4-oxadiazol-5-yl)methylcarbamate (61-2)

A solution of crude compound 61-1 (˜1 g) and TBAF (1.05 g, 4 mmol) inTHF (50 mL) was heated under reflux for 4 h. The mixture was cooled toroom temperature, then concentrated to dryness. The residue was purifiedby silica gel chromatography (EtOAc/Hexane/DCM=1:2:1) and affordedcompound 61-2 (220 mg, 26% yield from compound 45-1).

Step 3:(4-(5-(Aminomethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)(1H-indol-3-yl)methanone (PTC17341-107, ARI-138)

This compound was synthesized according to the protocol described inExample 71 from compound 61-2 (220 mg, 0.52 mmol) to give title compoundPTC17341-107 (ARI-138) in the form of a yellow solid (70% yield). ¹H-NMR(400 MHz, DMSO-d6): δ 12.39 (bs, 1H), 9.15 (s, 1H), 8.80 (s, 1H),8.32˜8.35 (m, 1H), 7.60˜7.62 (d, J=5.6 Hz, 1H), 7.30˜7.32 (m, 2H), 4.08(s, 2H), 2.23 (s, 2H). LC-MS: m/z 326.4 [M+H]⁺.

Example 116: Preparation of2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-5-aminooxazole-4-carbonitrile(PTC17341-109, ARI-139)

ARI-139 was synthesized according to the scheme of FIG. 35 and by thefollowing method:

Step 1: tert-butyl3-(4-(5-amino-4-cyanooxazol-2-yl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(64-1)

Oxalyl chloride (890 mg, 5.3 mmol) was added to a suspension of compound1-5 (1.3 g, 3.5 mmol) in DCM (20 mL) at 0° C. The mixture was allowed towarm to room temperature and stirred 5 h. The mixture was concentratedto dryness. The residue was dissolved in N-methyl-2-pyrrolidone (NMP) (5mL) and 2-aminomalononitrile 4-methylbenzenesulfonate (1.15 g, 4.5 mmol)was added to at room temperature. The resulting mixture was stirred for1 h. The mixture was diluted with H₂O (20 mL), extracted with EtOAc/THF(1:1, 30 mL×3). The combined organic phases were washed with brine (50mL×2), dried, concentrated to dryness. The residue was purified bysilica gel chromatography (EtOAc/Hexane/DCM=1:1:1) and afforded compound64-1 (440 mg, 29% yield).

Step 2:2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-5-aminooxazole-4-carbonitrile(PTC17341-109, ARI-139)

Compound 64-1 (440 mg, 1 mmol) was dissolved in THF (5 mL) and MeOH (5mL), KHCO₃ (1.0 g) and Na₂CO₃ (1.0 g) were added. The mixture wasstirred overnight at room temperature. The mixture was diluted with H₂O(20 mL), extracted with EtOAc/THF (1:1, 30 mL×3). The combined organicphases were washed with brine (50 mL×2), dried, concentrated to dryness.The residue was triturated with EtOAc (20 mL) and MeOH (20 mL) to givetitle compound PTC17341-109 (ARI-139) in the form of a yellow solid (190mg, 57% yield). ¹H-NMR (400 MHz, DMSO-d6): δ12.38 (bs, 1H), 9.08˜9.10(d, J=2.8 Hz, 1H), 8.48 (s, 1H), 8.30˜9.34 (m, 1H), 8.17 (s, 1H),7.58˜7.62 (d, J=6.4 Hz, 1H), 7.29˜7.33 (m, 2H). LC-MS: m/z 326.4 [M+H]⁺.

Example 117: Preparation of1-(2-(7-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-140)

Starting with 7-fluoroindole and using the procedure described inExample 84-Step 6, the title compound was prepared.

Example 118: Preparation of methyl 2-(5-cyano-1H-indole-3-carbonyl)thiazole-4-carboxylate (PTC17341-60) (ARI-141)

ARI-141 was synthesized according to the scheme of FIG. 36 and by thefollowing method:

Step 1: Methyl 2-(5-bromo-1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl)thiazole-4-carboxylate (75-1)

This compound was synthesized according to the protocol described inExample 65 from compound 10-5 (1.0 g, 2.2 mmol) to give title compound75-1 in the form of an off-white solid (0.93 g, 91% yield).

Step 2: Methyl 2-(1-(tert-butoxycarbonyl)-5-cyano-1H-indole-3-carbonyl)thiazole-4-carboxylate (75-2)

A mixture of compound 75-1 (800 mg, 1.7 mmol), Zn(CN)₂ (600 mg, 5.2mmol), actived Zn (28 mg, 0.4 mmol) and fresh prepared Pd(PPh₃)₄ (0.5 g)in dry DMF (30 mL) was stirred at 120° C. under a nitrogen atmosphereovernight. The reaction mixture was cooled to room temperature andquenched with H₂O (50 mL), then extracted with EtOAc/THF (1:1, 50 mL×3).The combined organic phases were washed with brine (50 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to afford crude.The crude was triturated with EtOAc (20 mL), filtered, dried and afford75-2 (250 mg, 35% yield).

Step 3: Methyl 2-(5-cyano-1H-indole-3-carbonyl)thiazole-4-carboxylate(PTC17341-60, ARI-141)

This compound was synthesized according to the protocol described inExample 71 from compound 75-2 (250 mg, 0.6 mmol) to give title compoundin the form of a yellow solid (65% yield). ¹H-NMR (400 MHz, DMSO-d6): δ12.78 (bs, 1H), 9.22 (s, 1H), 8.95 (s, 1H), 8.66 (s, 1H), 7.78˜7.82 (d,J=8.4 Hz, 1H), 7.68˜7.72 (d, J=8.4 Hz, 1H), 3.93 (s, 3H). LC-MS: m/z310.1 [M−H]⁻.

Example 119: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5-fluoro-1H-indol-3-yl)methanone(ARI-148)

Starting with 5-fluoroindole and using the procedure described inExample 131 the title compound was prepared.

Example 120: Preparation of1-(2-(4-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-142)

Starting with 4-fluoroindole and using the procedure described inExample 84-Step 6, the title compound was prepared.

Example 121: Preparation of5-amino-2-(2-(7-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)oxazole-4-carbonitrile(ARI-144)

Starting with 2-(1H-indole-7-fluoro-3-carbonyl)thiazole-4-carboxylicacid and using the method described in Example 116 the title compoundwas prepared.

Example 122: Preparation of(4-(5-(aminomethyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(7-fluoro-1H-indol-3-yl)methanone(ARI-145)

Starting with 2-(1H-indole-7-fluoro-3-carbonyl)thiazole-4-carboxylateand using the procedure outlined in Example 114, the title compound wasprepared.

Example 123: Preparation of(4-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)thiazol-2-yl)(7-fluoro-1H-indol-3-yl)methanone(ARI-146)

Starting with 2-(1H-indole-7-fluoro-3-carbonyl)thiazole-4-hydroxyamidateand using the procedure described in Example 115 the title compound wasprepared.

Example 124: Preparation of5-amino-2-(2-(5-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)oxazole-4-carbonitrile(ARI-147)

Starting with 2-(1H-indole-5-fluoro-3-carbonyl)thiazole-4-carboxylicacid and the procedure described in Example 116 the title compound wasprepared.

Example 125: Preparation of1-(2-(5,6-difluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one(ARI-149)

ARI-149 was synthesized according to the scheme of FIG. 37 and by thefollowing method. Potassium tert-butoxide (1.76 g, 16 mmol) was added toa solution of 6,7-difluoroindole (2.0 g, 13 mmol) in THF (100 mL) at 0°C. under N₂. The mixture was stirred for 1 h at this temperature, andthen a solution of compound 70-5 (2.6 g, 13 mmol) in THF (20 mL) wasadded to it at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was quenched withsaturated NH₄Cl aqueous (100 mL), stirred for 20 min, and filtered. Thesolid was collected, washed with water (30 mL×3), EtOAc (30 mL×3) andMeOH (30 mL×3), dried to afford ARI-149 (459 mg, 11% yield) as yellowsolid. ¹H-NMR (400 MHz, DMSO-d6): δ 12.43 (bs, 1H), 9.19 (s, 1H), 8.87(s, 1H), 8.13˜8.19 (m, 1H), 7.6˜47.70 (m, 1H), 3.21˜3.28 (q, J=7.2 Hz,2H), 1.13˜1.18 (t, J=7.2 Hz, 3H). LC-MS: m/z 319.4 [M−H]⁻.

Example 126: Preparation of1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-methylpropan-1-one (ARI-048)

Starting with 2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid andisopropylmagnesium bromide instead of methylmagnesium bromide using theprocedure described in Example 75 the title compound was prepared.

Example 127: Preparation of (1H-indol-3-yl)(4-(1-(methoxyimino)propyl)thiazol-2-yl) methanone (PTC17341-21, ARI-054)

ARI-054 was synthesized according to the scheme of FIG. 38 and by thefollowing method:

Step 1: tert-Butyl3-((4-propionylthiazol-2-yl)(trimethylsilyloxy)methyl)-1H-indole-1-carboxylate(79-1)

EtMgBr (2M in Et₂O, 40 mL, 80 mmol) was added portionwise to a solutionof compound 40-2 (13.0 g, 26.6 mmol) in THF (200 mL) at 0° C. over 30min. The resulting mixture was stirred for 0.5 h, then quenched withsaturated aqueous NH₄Cl (500 mL), extracted with EtOAc (250 mL×3). Thecombined organic phases were washed with brine (500 mL×2), dried,concentrated to afford 79-1 (12.8 g, ˜100% yield) as an oil, which wasused for next step without further purification.

Step 2: tert-Butyl3-((4-(1-(methoxyimino)propyl)thiazol-2-yl)(trimethylsilyloxy)methyl)-1H-indole-1-carboxylate (79-2)

NaOAc (722 mg, 8.8 mmol) and methoxylamine hydrochloride (355 mg, 4.2mmol) were added to a solution of compound 79-1 (1.0 g, 2.2 mmol) inEtOH (5 mL) and H₂O (15 mL) at room temperature. The mixture was heatedto 70° C. and stirred for 2 h. After cooled to room temperature, themixture was concentrated in vacuo. The residue was purified by silicagel column chromatography (hexane/EtOAc=5:1) to give compound 79-2 (340mg, 32% yield).

Step 3: tert-Butyl3-(hydroxy(4-(1-(methoxyimino)propyl)thiazol-2-yl)methyl)-1H-indole-1-carboxylate(79-3)

Compound 79-2 (340 mg, 0.7 mmol) was dissolved in THF (20 mL), TBAF (200mg, 0.77 mmol) was added. The mixture was stirred for 2 h at roomtemperature, then quenched with water (50 mL), extracted with EtOAc (50mL×3). The combined organic phases were washed with brine (100 mL×2),dried, concentrated to dryness. The residue was purified by silica gelchromatography (EtOAc/Hexane=1:3) and afforded compound 79-3 (210 mg,72% yield).

Step 4: tert-Butyl3-(4-(1-(methoxyimino)propyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(79-4)

This compound was synthesized according to the protocol described inExample 75 from compound 79-3 (470 mg, 1.1 mmol) to give title compound79-4 in the form of a yellow solid (268 mg, 57% yield).

Step 5: 1H-Indol-3-yl)(4-(1-(methoxyimino)propyl)thiazol-2-yl)methanone(PTC17341-21, ARI-054)

This compound was synthesized according to the protocol described inExample 71 from compound 79-4 (268 mg, 0.65 mmol) to give title compoundPTC17341-21 (ARI-054) in the form of a yellow solid (95 mg, 47% yield).¹H-NMR (400 MHz, DMSO-d6): δ 12.32 (bs, 1H), 9.07 (s, 1H), 8.31˜8.34 (m,2H), 7.56˜7.59 (m, 1H), 7.27˜7.31 (m, 1H), 3.97 (s, 3H), 2.86˜2.94 (q,J=7.6 Hz, 2H), 1.14˜1.25 (m, 3H). LC-MS: m/z 314.3 [M+H]⁺.

Example 128: Preparation of1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-143)

Starting with 6-fluoroindole and using the method described in Example84-Step 6, the title compound was prepared.

Example 129: Preparation of1-(2-(5,7-difluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one(ARI-150)

ARI-150 was synthesized according to the scheme of FIG. 39 and theprotocol described in Example 84 from compound 70-7 (2.05 g, 10 mmol)and 5,7-difluoroindole to give title compound ARI-150 in the form of ayellow solid (1.51 g, 48% yield). ¹H-NMR (400 MHz, DMSO-d6): δ 13.11(bs, 1H), 9.19 (s, 1H), 8.88 (s, 1H), 7.83˜7.87 (m, 1H), 7.24˜7.31 (m,1H), 3.23˜3.28 (q, J=7.2 Hz, 2H), 1.13˜1.18 (t, J=7.2 Hz, 3H). LC-MS:m/z 318.9 [M−H]⁻

Example 130: Preparation of2-(1-(tert-butoxycarbonyl)-1H-indole-3-carbonyl) thiazole-4-carboxylicAcid (1-5)

This compound was synthesized according to the scheme of FIG. 40 and bythe following method:

Step 1: tert-Butyl 3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate(1-1)

Oxalyl chloride (473.3 g, 3.73 mol) was added dropwise to a suspensionof indol-3-carboxylic acid (400.0 g, 2.48 mol) in DCM (4 L) at 0° C.over 1 h. The mixture was allowed to warm to room temperature andstirred overnight. The mixture was concentrated to dryness to afford1H-indole-3-carbonyl chloride (446.0 g).

The above 1H-indole-3-carbonyl chloride (446.0 g) was added portion-wiseto a suspension of N,O-dimethylhydroxylamine hydrochloride (266.0 g,2.73 mol) and TEA (551.1 g, 5.46 mol) in DCM (5 L) at room temperatureover 1 h. The mixture was stirred overnight, then quenched with water (2L). The organic phase was collected and washed with water (2 L×2),saturated aqueous NaHCO₃ (2 L×2), and brine (2 L×1), dried (Na₂SO₄),filtered and concentrated to dryness. The residue and DMAP (15.1 g,0.124 mol) was dissolved in DMF (1 L) and DCM (4 L), cooled to 0° C.Boc₂O (540.64 g, 2.48) and DMAP (15.1 g, 0.124 mol) were added dropwiseto over 1 h. The resulting mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was quenched with water(2 L). The organic phase was separated and washed with water (2 L×2),saturated aqueous NaHCO₃ (2 L×2), and brine (2 L×1), dried (Na₂SO₄),filtered and concentrated to dryness. The residue was triturated withEtOAc/hexane (1:5, 1 L), filtered and dried to afford compound 1-1(557.9 g, 75% yield) as off-white solid. ¹H-NMR (400 MHz, DMSO-d6): δ9.40 (s, 1H), 8.72 (s, 1H), 8.36˜8.38 (m 1H), 8.15˜8.18 (d, J=8.0 Hz,1H), 7.40˜7.50 (m, 2H), 3.80 (s, 3H), 3.40 (s, 3H), 1.69 (s, 9H).

Step 2: tert-Butyl3-(4-((tert-butyldimethylsilyloxy)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(1-2)

A solution of 2-bromo-4-((tert-butyldimethylsilyloxy)methyl)thiazole(135.0 g, 0.44 mol) in THF (1.5 L) was cooled to −78° C., and n-BuLi(1.6 M solution in hexane, 385 mL, 0.62 mol) was added dropwise at −78°C. over 1 h. The mixture was stirred for 0.5 h at this temperature, thena solution of compound 1-1 (120.0 g, 0.4 mol) in THF (500 mL) was addeddropwise over 1 h. The mixture was stirred at −78° for 1 h then allowedto warm to 0° C. and quenched with aqueous 10% NH₄Cl (1 L). The organicphase was collected and washed with water (1 L×2), saturated aqueousNaHCO₃ (1 L×2), and brine (1 L×1), dried (Na₂SO₄), filtered andconcentrated to dryness. The residue was triturated with EtOAc/hexane(1:5, 500 mL), filtered and dried to afford compound 1-2 (132.0 g, 70%yield) as off-white solid.

Step 3: tert-Butyl3-(4-(hydroxymethyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate (1-3)

A solution of compound 1-2 (91.0 g, 0.19 mol) in THF (500 mL) andpyridine (50 mL) was cooled to 0° C., and HF-pyridine (30%, 50 mL) wasadded dropwise over 10 min. The mixture was stirred for 0.5 h at thistemperature, then allowed to warm to room temperature and stirredovernight. The mixture was quenched with aqueous 10% NH₄Cl (1 L) andEtOAc (500 mL). The organic phase was collected and washed with water(500 mL×2), saturated aqueous NaHCO₃ (500 mL×2), and brine (500 mL×1),dried (Na₂SO₄), filtered and concentrated to dryness. The residue wastriturated with EtOAc/hexane (1:5, 100 mL), filtered and dried to affordcompound 1-3 (49.6 g, 73% yield) as off-white solid.

Step 4: tert-Butyl3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (1-4)

Dess-Martin periodinane (DMP, 26.1 g, 61 mmol) was added to a solutionof compound 1-3 (20.0 g, 56 mmol) in DCM (350 mL) at 0° C. The mixturewas stirred for 0.5 h at this temperature, then allowed to warm to roomtemperature and stirred overnight. The mixture was diluted with aqueousH₂O (500 mL) and DCM (500 mL), then filtered. The cake was washed withDCM (200 mL×3). The filtrate and washing were separated and the organicphase was collected, washed with aqueous 5% KHSO₄ (500 mL×3), saturatedaqueous NaHCO₃ (500 mL×3), and brine (500 mL×1), dried (Na₂SO₄),filtered and concentrated to dryness. The residue was triturated withEtOAc/hexane (1:2, 50 mL), filtered and dried to afford compound 1-4(20.2 g, 93% yield) as off-white solid. ¹H-NMR (400 MHz, DMSO-d6): δ10.06 (s, 1H), 9.52 (s, 1H), 9.12 (s, 1H), 8.35˜8.40 (d, J=7.6 Hz, 1H),8.14˜8.17 (d, J=8.0 Hz, 1H), 7.40˜7.50 (m, 2H), 1.71 (s, 9H). LC-MS:m/z: 357.4 [M+H]⁺

Example 131: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5,6-difluoro-1H-indol-3-yl)methanone(ARI-154)

ARI-154 was synthesized according to the scheme of FIG. 41 and by thefollowing method:

Step 1: 5,6-Difluoro-1H-indole-3-carboxylic Acids (91-1)

Trifluoroacetic anhydride (38 mL, 56.0 g, 0.27 mol) was added dropwiseto a solution of 5,6-difluoro-1H-indole (0.22 mol) in DMF (300 mL) over0.5 h at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was quenched with water(1 L), many solid began to form, the mixture was stirred for 0.5 h, thenfiltered. The solid was collected, washed with water (200 mL×3), thenadded to aqueous sodium hydroxide (20%, 150 mL, 0.75 mol) and heatedunder reflux for 8 h. The reaction mixture was cooled and acidified withaqueous 3N HCl to pH of 3. Many solid began to form. The solid wascollected by filter, washed with water (200 mL×3), dried to give titlecompound 91-1 (15.53 g, 59% yield).

Steps 2/3/4:2-(1-(tert-butoxycarbonyl)-5,6-difluoro-1H-indole-3-carbonyl)thiazole-4-carboxylic acid (91-4)

This compound was synthesized according to the protocol described inExample 130 from compound 91-1 (8.80 g, 44 mmol) to give title compound91-4 in 36% yield.

Step 5: tert-Butyl3-(4-(2-(tert-butoxycarbonyl)hydrazinocarbonyl)thiazole-2-carbonyl)-5,6-difluoro-1H-indole-1-carboxylate(91-5)

HATU (3.60 g, 95 mmol) and DIPEA (2.80 g, 22 mmol) were added to asuspension of compound 91-4 (3.00 g, 7.3 mmol) and Boc-hydrazine (1.50g, 11 mmol) in DMF (20 mL) at 0° C. The mixture was allowed to warm toroom temperature and stirred for 5 h. The mixture was diluted with H₂O(100 mL), extracted with EtOAc (100 mL×3). The combined organic phaseswere washed with brine (100 mL×2), dried, concentrated to dryness. Theresidue was purified by silica gel chromatography (EtOAc/Hexane=1:2 to1:1) and afforded compound 91-5 (1.61 g, 42% yield).

Step 6: 2-(5,6-difluoro-1H-indole-3-carbonyl)thiazole-4-carbohydrazide(91-6)

A solution of compound 91-6 (1.60 g, 3 mmol) in DCM (50 mL) and TFA (50mL) was stirred at room temperature for 3 h. The mixture concentrated todryness. The residue was suspended in EtOAc (20 mL), alkalified bysaturated aqueous NaHCO₃ to pH of 7˜8. The mixture was filtered tocollect the solid. The solid was washed with water (10 mL×3) and EtOAc(10 mL×3), dried to afford 91-6 (0.92 g, 95% yield).

Step 7:(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5,6-difluoro-1H-indol-3-yl)methanone (ARI-154)

BrCN (0.50 g, 4.5 mmol) was added to a suspension of compound 91-6 (0.90g, 2.8 mmol) in EtOH (250 mL) at room temperature. The mixture washeated to 65° C. and stirred for 20 h. After cooled to room temperature,the mixture was filtered to collect the solid. The solid was washed withEtOH (10 mL×3), dried to afford ARI-154 (520 mg, 52% yield) as yellowsolid. 1H-NMR (400 MHz, DMSO-d6): δ12.55 (bs, 1H), 9.11 (s, 1H), 8.58(s, 1H), 8.13˜8.16 (m, 1H), 7.6˜77.70 (m, 1H), 7.44 (s, 2H). LC-MS: m/z346.0 [M−H]⁻.

Example 132: Preparation of methyl2-(5-methoxy-1H-indole-3-carbonyl)thiazole-4-carboxylate (ARI-080)

Starting with 2-(5-methoxy-1H-indole-3-carbonyl)thiazole-4-carboxylateand the method described in Example 65, the title compound was prepared.

Example 133: Preparation of(4-(5-amino-1,3,4-oxadiazol-2-yl)thiazol-2-yl)(5-fluoro-2-methyl-1H-indol-3-yl)methanone(ARI-135)

Starting with 5-fluoro-2-methyl-1H-indole and the method described inExample 131, the title compound was prepared.

Example 134: Preparation of(2-(1H-indole-3-carbonyl)thiazol-4-yl)(3-hydroxyazetidine-1-yl)methanone(ARI-045)

Using azetidine-3-ol instead of ethylamine and the method described inExample 24, the title compound was prepared.

Example 135: Dibromo Indole Compounds

5,7-dibromo indole 3-carboxylic acid may be prepared according to Katneret al., “An Improved Synthesis of Indole-3-Carboxylic Acids,” OrganicPreparations and Procedures Vol. 2, Iss. 4, 1970, incorporated herein byreference in its entirety. FIG. 42 shows a scheme of synthesizingdibromo indole compounds.

Example 136: Modification of the Thiazole and Ester Fragments toPotentially Slow Down Ester Hydrolysis

FIG. 43 shows exemplary indole compounds where thiazole and esterfragments are modified to potentially slow ester hydrolysis. Thecompounds can be synthesized using cysteine derivatives, such as L and Dpenicillamine and 2-amino-3-sulfanyl butanoic acid, which arecommercially available.

Example 137: Synthesis of ARI-1073 and ARI-024

FIG. 44 describes a route of synthesis for ARI-1073 and ARI-024.

Example 138: Synthesis of ARI-068, ARI-092, and ARI-094

FIG. 45 illustrates a synthesis route for ARI-068, ARI-092, and ARI-094.

Example 139: Synthesis of ARI-1029 and ARI-1030

FIG. 46 illustrates a synthesis route for ARI-1029 and ARI-1030.

Example 140: Synthesis of Amino Amides and Cyclic Versions of IndoleCompounds

FIG. 47 illustrates a synthesis route for amino amides and cyclicversions of indole compounds.

Example 141: Synthesis of Oxime Compounds with Hindered Ketones

FIG. 48 illustrates a synthesis route for oxime compounds with hinderedketones. Additional routes to hindered ketones are shown in FIG. 59.

Example 142: Synthesis of Pyrazine Compounds

FIG. 49 illustrates a synthesis route for pyrazine compounds.

Example 143: Properties of Compounds with Thiazole and IndoleReplacements

FIG. 50 compares the properties of compounds with thiazole and indolereplacements.

Example 144: Synthesis of ARI-020

FIG. 51 illustrates a synthesis scheme of ARI-020 (corresponding toproduct 3 in the synthesis scheme). According to this scheme, the yieldof product 2 from 300 mg starting material 1 was 224 mg (70%). 1H NMRand MS results were consistent. Additionally, the yield of product 3from 224 mg of starting material 2 was 45 mg (27%). ARI-020 was isolatedas a lyophilized white solid with an HPLC purity >99%. The structure wasconfirmed by 1H NMR and MS.

Example 145: Synthesis of ARI-018

FIG. 52 illustrates a synthesis scheme of ARI-018 (corresponding toproduct 3 in the synthesis scheme). According to this scheme, the yieldof product 2 (a mixture of E/Z isomers) from 300 mg starting material 1was 230 mg (74%).

Example 146: Synthesis of ARI-019

FIG. 53 illustrates a synthesis scheme of ARI-019 (corresponding toproduct 3 in the synthesis scheme). According to this scheme, the yieldof product 2 from starting material 1 was 36%; and the yield of product3 from starting material 2 was 22%. The synthesized ARI-019 was isolatedin 90% HPLC purity after 2 columns.

Example 147: Synthesis of ARI-017

FIG. 54 illustrates a synthesis scheme of ARI-017 (corresponding toproduct 3 in the synthesis scheme). According to this scheme, the yieldof product 2 (E/Z isomers after column) from 300 mg starting material 1was 277 mg (86%).

Example 148: Synthesis of ARI-030

FIG. 55 illustrates a synthesis scheme for the preparation of ARI-030(corresponding to product 4 in the synthesis scheme).

Example 149: Synthesis of an Aldehyde Intermediate

FIG. 56 shows a synthesis scheme of an aldehyde intermediate.

Example 150: Synthesis of ARI-021

FIG. 57 illustrates a synthesis scheme for the preparation of ARI-021(corresponding to product 3 in the synthesis Scheme B). Scheme A showsBoc protection of the starting carboxylic acid, with a yield of 81%(product 1). Scheme B shows the subsequent Curtius reaction on product1, with a yield of product 2 from starting material 1 (0.266 g) of 113mg (48%). 1H NMR and MS results were consistent with the proposedstructure.

Example 151: Synthesis of ARI-1057

FIG. 58 illustrates a synthesis scheme of ARI-1057 (corresponding toproduct 4 in the synthesis scheme).

Example 152: Stimulation of CYP1A1 in Human HepG2 Cells and MouseHepa1-6 Cells

CYP1A1 induction is under the control of the AhR signaling pathway. ThisExample describes an in vitro assay (7-ethoxy-resorufin-O-deethylase(EROD) assay) that evaluated the AhR modulating activities of the indolecompounds described herein. In this assay, the indole compounds wereincubated with human HepG2 cells or mouse Hepa1-6 cells. The activity ofCYP1A1 in the cells was measured by the conversion of substrate7-ethoxyresorufin, with the readout being a fluorescence signalassociated with the conversion product. The EC₅₀ values of the indolecompounds as well as the maximum luminescence induced by them in theassay were determined.

Materials

Human HepG2 cells were obtained from Sigma Aldrich (Catalog85011430-1VL). Mouse Hepa1-6 cells also were obtained from Sigma Aldrich(Catalog 92110305-1V).

Methods

Human HepG2 and Mouse Hepa1-6 cells were grown to 60-80% confluency intissue culture flasks, lifted with non-enzymatic cell dissociationsolution (cell stripper), seeded in a 384-well plate at 5,000 cells perwell, treated with the test compounds, and incubated for 20 hoursovernight at 37° C. The treatment medium was removed and a solution ofsubstrate 7-ethoxyresorufin (ETX) was added to initiate the reaction.The plate was incubated at 37° C. for 30 minutes. The reaction wassubsequently terminated by adding tempered methanol. Fluorescentemission was measured at 590 nm with excitation at 530 nm in aFLEXSTATION III instrument (Molecular Devices).

Results

Table 3 shows the EROD assay data of ARI-001 (ITE), ARI-002, and ARI-002derivatives ARI-087, ARI-140, ARI-142, ARI-143, and ARI-149 using humanHepG2 cells and mouse Hepa1-6 cells, respectively. The data for eachcell line were obtained from the same plates.

TABLE 3 EROD Assay Data Compound EC₅₀ (nM) EC₅₀ (nM) ID in HepG2 inHepa1-6 ARI-001 28.9 64.0 ARI-002 19.1 6.5 ARI-087 34.2 5.8 ARI-140 0.719.5 ARI-142 64.8 12.8 ARI-143 4.2 2.3 ARI-149 19.2 0.6

The results from the above table show that in human HepG2 cells,ARI-087, ARI-140, ARI-143 and ARI-149 had EC₅₀ values that were similarto or lower than that of ARI-001 or ARI-002. ARI-142 was less activethan ARI-002. Similar results were observed in the mouse Hepa1-6 cellassay, except that in that assay, ARI-140 was shown to be less activethan ARI-002.

The human EROD assay shows that indole compounds comprising anoxadiazole moiety such as ARI-030, ARI-031, ARI-056, ARI-060, ARI-083,ARI-090, ARI-118, ARI-120, ARI-145, and ARI-148 were significantly more(about 4 to 900 times more) active than ARI-001, while ARI-146 wassimilar in activity to ARI-001. These more active oxadiazole derivativesof ITE could be categorized into three groups, based on their EC₅₀values, in the order of increasing activity: (1) active: ARI-030(5-methyl-1,2,4-oxadiazole), ARI-031 (3-methyl-1,2,4-oxadiazole),ARI-056 (1,3,4-oxadiazole) and ARI-060 (2-methyl-1,3,4 oxadiazole); (2)more active: ARI-083 (2-amino-1,3,4-oxadiazole), ARI-090(2-amino-1,3,4-thiadiazole), ARI-145(7-fluoroindolo-2-aminomethyl-1,3,4-oxadiazole), and ARI-148(5-fluoroindolo-2-amino-1,3,4 oxadiazole); and (3) most active: ARI-118(7-fluoroindolo-2-amino-1,3,4 oxadiazole ARI-118) and ARI-120(5,6-dichloroindolo-2-amino-1,3,4 oxadiazole). ARI-002 was similarlyactive as the compounds in group (2). Of note, in this assay, ARI-118was about 930 times more active than ARI-001 and about 13 times moreactive than ARI-002. Similar to the human EROD assay, the mouse ERODassay shows that ARI-118, ARI-120, and ARI-145 were the most activeamong the tested oxadiazole compounds.

The human and mouse EROD assays also show that ARI-004, ARI-049,ARI-055, ARI-065, ARI-066, and ARI-067 were less active—in many casessignificantly less so—than ARI-002.

Example 153: Suppression of IL-21 Secretion by Activated Th17 Cells

IL-21 is a pro-inflammatory cytokine secreted by CD4⁺ Th17 cells and isthought to serve as a T-cell growth factor playing overlapping roleswith IL-2. This Example describes a study that measured the IC₅₀ valuesof the indole compounds disclosed herein for suppressing IL-21 secretionfrom human CD4⁺ T cells that had been treated with stimulatoryconditions that gave rise to TH17 cells (see, e.g., Dobritsa et al., JBiomol Screen. 18(1):75-84 (2013)).

Materials

Human CD4⁺ T cells were purchased from Lonza Walkersville Inc.(Walkersville, Md.). DMSO was obtained from Sigma (St. Louis, Mo.).Greiner cell culture plates, Gibco DMEM cell culture medium, mediasupplements, and antibiotics, as well as DYNABEADS Human T-ActivatorCD3/CD28 and R&D Systems TGF-β, IL-1β and IL-23 and Invitrogen IL-6cytokines, were purchased through Fisher Scientific (Pittsburgh, Pa.).ALPHALISA assay plates and the Human Interleukin-21 ALPHALISA kit wasobtained from Perkin Elmer (Boston, Mass.).

Methods

Cell Culture Conditions and Treatment

Cell culture plates were pre-coated with test compounds in serialdilutions for generating a 10-point, 3-fold dose response curve with atop concentration of 1 μM or 100 nM. To do this, compounds weredissolved in DMSO and added to an ECHO qualified plate for transfer tothe cell culture plate with the ECHO555. The indole compounds to betested were dissolved in water and wells were backfilled with DMSO sothat all treatments received 0.1% DMSO final volume. Positive control(0% inhibition) wells, in which compounds were replaced with 1.0% DMSO,were included on each plate. At least 15×10⁶ frozen CD4⁺ T cells perplate of compounds were thawed in a 37° C. water bath, and the cellswere washed twice with 10 mL of the complete medium (DMEM supplementedwith 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 μg/mLstreptomycin), followed by centrifugation (250×g, 10 min). Cells werere-suspended to the desired density, and cultured in 384-well treatedsterile cell culture plates in a total volume of 50 μL per well. Eachplate included wells with induced and un-induced cells.

Induced cells were activated in the complete medium with DYNABEADS HumanT-Activator CD3/CD28 at a bead-to-cell ratio of 1:2.5 and stimulatedwith the following cytokines: transforming growth factor-β (TGF-β, 5ng/mL), IL-6 (20 ng/mL), IL-23 (20 ng/mL), and IL-1β (10 ng/mL).

Un-induced cells were left in complete medium with no additionalsupplements. Plates were incubated at 37° C., 5% CO₂ for a total of 5days. Upon completion of the 5 day incubation period, cells were spundown (1,000×g, 1 min) and supernatant was transferred to the ALPHALISAassay plate using the Mosquito HTS liquid handler (TTP Labtech Inc.,Cambridge, Mass.).

IL-21 ALPHALISA Assay

IL-21 levels in cell supernatants and cell-free control samples weremeasured using the ALPHALISA assay kit from Perkin Elmer, following themanufacturer's instructions. The assay was run at room temperature in384-well ALPHAPLATES (cat. 6005350; Boston, Mass.). Briefly, immediatelyafter transferring the cell supernatant to the assay plate, anti-IL-21acceptor beads were added with the CERTUS FLEX liquid handler (LEAPTechnologies, Morrisville, N.C.). The plate was sealed, spun down andincubated for 30 minutes. After incubation, the seal was removed,anti-IL-21 biotinylated antibody was added with the CERTUS FLEX, and theplate was sealed again, spun down and incubated for 60 minutes. Next,the seal was removed, streptavidin-coated donor beads were added withthe CERTUS FLEX, and the plate was sealed, spun down and incubated foranother 60 minutes. Finally, the seal was removed and the plate was readusing the ENVISION reader (Perkin Elmer, Boston, Mass.) set with anexcitation filter of 680 nm and an emission filter of 615 nm. Twoindependent IL-21 standard dilution curves were run per plate withanalyte provided in the ALPHALISA kit.

Data Analysis

For estimation of the assay performance, Z′ values were calculated foreach plate, comparing positive and negative controls. A Z′ value ≥0.5was chosen as the acceptance cutoff. The XLfit 5.2.0.0 software (IDBS,Guildford, UK) was used for curve fitting. IC₅₀ values were calculatedusing a four-parameter logistic fit model, model 205, and IL-21 standardcurves were fitted using a linear polynomial model, model 100.

Results

Table 4 shows the IC₅₀ (nM) values of the various indole compoundsherein for suppression IL-21 secretion.

TABLE 4 Suppression of IL-21 Secretion Compound IC₅₀ Analog Series ID(nM) Esters ARI-001 38.2 ARI-055 73.6 ARI-066 48.6 Ketones ARI-002 31.8ARI-067 6.3 ARI-087 25.4 ARI-140 8.6 ARI-142 208.8 ARI-143 18.8 ARI-14930.3 Oxa-or ARI-030 40.0 thia-diazoles ARI-031 42.6 ARI-056 4.9 ARI-060110.0 ARI-083 0.3 ARI-090 8.4 ARI-118 0.8 ARI-120 0.3 ARI-145 46.9ARI-146 13.4 ARI-148 5.9 Amides ARI-004 231.1 ARI-049 10.1 ARI-065 14.0

The above table shows that in the ketone series, ARI-067, ARI-087,ARI-140, ARI-143 and ARI-149 all had IC₅₀ values similar to or lowerthan that of ARI-002. ARI-142 was the least active in suppressing IL-21secretion. These data are consistent with the EROD data described above,except for ARI-140, which showed less activity in the mouse EROD assay,as noted previously. Overall, however, there was high concordancebetween both assays.

In the oxa- or thia-diazole series, ARI-30, ARI-031, and ARI-060 wereamong the least potent, as also shown in the EROD assays describedabove. ARI-083, ARI-118, and ARI-120 were the most potent. Notably,ARI-118 was about 32 times more potent than ARI-087 in this assay.ARI-118 and ARI-120 also were shown to be in the most active group inthe EROD assays.

The above IL-21 secretion data also shows that while ARI-004 had weakactivity, adding a 5-chloro or 5-fluoro group at its indole ringsignificantly improved its activity. However, the same modification didnot improve ARI-001's activity (ester series) meaningfully.

Example 154: Determination of Metabolic Stability of Indole Compounds

The liver is an important organ in the body for drug metabolism. ThisExample describes hepatocyte intrinsic clearance assays using both humanand mouse hepatocytes to evaluate the metabolic stability of the indolecompounds disclosed herein. The parameters measured include t_(1/2)(half-life), CL_(int) (intrinsic clearance), and E_(H) (hepaticextraction ratio).

Materials

Testosterone (Lot FE111011-01) was obtained from Cerilliant (Round Rock,Tex.). 7-hydroxycoumarin (Lot 11631ED) was obtained from Sigma Aldrich(St. Louis, Mo.). Cryopreserved human hepatocytes pooled from ten donormales (X008001), cryopreserved male IRC/CD-1 mouse hepatocytes(M005052), INVITROGRO HI Medium (incubation), and INVITROGRO HT Medium(thawing) were obtained from Bioreclamation IVT (Baltimore, Md.). Allsolvents were obtained from commercial sources and used without furtherpurification.

Methods

Metabolic Stability Hepatocytes

Each test compound was prepared as a 1 mM stock solution in DMSO. A 2 μMsolution of test compound and positive controls were prepared inINVITROGRO HI Medium (incubation). These solutions were pre-warmed in asterile incubator set to maintain 37° C., 5% CO₂, and 98% humidity.Cryopreserved hepatocytes were prepared at a concentration of 2×10⁶living cells/mL in incubation media and pre-warmed in the incubator. Thecompound solutions and hepatocyte mixtures were then combined at a ratioof 1:1 (v:v). The final volume of the reaction mixture was 750 μL,containing 1 μM test compound (10 μM for 7-hydroxycoumarin) and 1×10⁶cells. The reaction mixture was placed in the incubator on a plateshaker. After 0, 15, 30, 60, 90, and 120 minutes of incubation, 100 μLof reaction mixtures were removed from the incubation plate and mixedwith 150 μL of ice-cold acetonitrile in a designated well of a 96-wellcrash plate. The 96-well crash plate was placed on ice for 15 min, andsamples were centrifuged (3,600 RPM, 10 min, 4° C.) to precipitateprotein. The supernatants were diluted 1:1 (v:v) with water containing0.15 μM verapamil and/or 1 μM tolbutamide (internal standards forpositive and negative modes, respectively) in a 96-well shallowinjection plate. This plate was sealed for LC-MS analysis. Allmeasurements were done in duplicate.

LC-MS Analysis

Liquid Chromatography

Column: Waters Atlantis T3 Column, 100A, 3 μm, 2.1 mm×50 mm (Part#186003717). Mobile Phase A: Water with 0.1% formic acid. Mobile PhaseB: Acetonitrile with 0.1% formic acid. Flow Rate: 0.7 mL/minute.Gradient Program:

Time (min) % A % B 0.0 90 10 0.4 90 10 1.2 10 90 2.0 10 90 2.1 90 10 3.090 10

Total Run Time: 3 minutes. Autosampler: 10 μL injection volume.Autosampler Wash: A: 90% water, 10% acetonitrile; B: 90% acetonitrile,10% water.

Mass Spectrometer

Instrument: AB SCIEX API4000. Interface: Turbo Ionspray. Mode: Q1Multiple Ions. Method: 3.0 minute duration. Mass Spectrometer SourceSettings:

IS TEM CUR GS1 GS2 5500 550 20 50 50Data and CalculationsDetermination of t_(1/2), CL_(int), E_(H), and % R at 60 Minutes

The residual compound remaining (% R) was determined from LC-MS peakareas by comparison to the zero time point. Metabolic half-life(t_(1/2)) and intrinsic clearance (CL_(int)) values were calculated fromthe slope of the plot of ln (% R) vs. time and the concentration ofhepatocytes present in the incubation. Percent remaining at 60 minuteswas calculated by plugging in the 60 minute value into the slopeequation generated by the percent remaining time points.

Calculation of In Vivo Hepatic Clearance

In vivo hepatic clearance CL_(H) was calculated using the well stirredliver model according to the following equation:

${{CL}_{H} = \frac{Q_{H} \cdot f_{u} \cdot {CL}_{int}^{\prime}}{Q_{H} + {f_{u} \cdot {CL}_{int}^{\prime}}}},$where Q_(H) is the total liver blood flow, f_(u) is unbound fraction ofthe drug, and CL′_(int) is defined as follows:CL′ _(int) =CL _(int)×(10⁶ cells/g of liver weight)×(g liver weight/kgof body weight).In the first approximation, used in this study, f_(u)=1.

Hepatic extraction ratio E_(H) was calculated using the followingequation:

$E_{H} = \frac{{CL}_{H}}{Q_{H}}$Corresponding physiological parameters used in calculations for allspecies are shown below in Table 5.

TABLE 5 Physiological Parameters of Mammalian Species Used forCalculation of CL_(H) g liver wt/kg 10⁶ cells/g Q_(H) Species body wtliver wt (mL/min/kg body wt) Human 26 99 21 Mouse 55 128 120Results

Table 6 shows the t_(1/2), CL_(int), and E_(H) of various indolecompounds described herein as assayed on human and mouse hepatocytes.

TABLE 6 Metabolism of Indole Compounds Human Hepatocytes MouseHepatocytes Com- CL_(int) CL_(int) pound t_(1/2) (μL/min/ E_(H) t_(1/2)(μL/min/ E_(H) ID (min) 10⁶ ells) (%) (min) 10⁶ ells) (%) Ester SeriesARI-001 7.8 220.4 91 5.5 585.7 87 ARI-055 67.3 10.3 56 135.1 5.1 23ARI-066 7.0 98.7 92 13.4 51.9 75 Ketone Series ARI-002 12.5 137.2 86 3.4961.9 91 ARI-067 300.2 2.3 22 212.3 3.3 16 ARI-087 114.8 6.0 43 110.66.3 27 ARI-140 200 3.5 30 450 1.5 8.3 ARI-142 86 8.1 50 66 11 38 ARI-143154 4.5 36 306 2.3 12 ARI-149 132 5.3 39 238 2.9 15 Oxa-or ThiadiazoleSeries ARI-030 378.6 1.8 18 17.1 40.5 70 ARI-031 968.2 0.7 8 702.8 1.0 6ARI-056 39.2 17.7 68 26.8 25.8 60 ARI-060 273.2 2.5 24 138.2 5.0 23ARI-083 646.9 1.1 12 968.3 0.7 4 ARI-090 131.2 5.3 39 282.0 2.5 13ARI-118 927 0.7 8.4 842 0.8 4.6 ARI-120 921 0.8 8.5 811 0.9 4.8 ARI-145170 4.1 33 136 5.1 23 ARI-146 374 1.9 19 100 6.9 29 ARI-148 282 2.5 23190 3.6 18 Amide Series ARI-004 42.7 40.2 65 2.8 1,174.2 93 ARI-049232.9 3.0 27 95.2 7.3 30 ARI-065 91.0 7.6 48 97.3 7.1 29

These results indicate that ARI-002, a ketone analog of ARI-001 (ITE),had high clearance in both human and mouse hepatocytes, as indicated bythe high extraction ratio (E_(H)). By contrast, derivatives of ARI-002with fluorine or chlorine substitutions in the indole ring displayedmuch improved metabolic profiles. For example, in human hepatocytes,ARI-087 had 23 times lower clearance and two times lower E_(H) ascompared to ARI-002. In mouse hepatocytes, ARI-087 had 153 times lowerclearance and three times lower E_(H) as compared to ARI-002. Likewise,the clearance of ARI-143 was 30 times and 418 times lower than that ofARI-002 in human and mouse hepatocytes, respectively, and the E_(H) ofARI-143 was two times and eight times lower than that of ARI-002 inhuman and mouse hepatocytes, respectively.

The oxa- or thia-diazole series of compounds similarly had markedlyimproved metabolic profiles than ARI-001 and ARI-002. For example,ARI-031, ARI-118, and ARI-120 had low clearance, as indicated by, e.g.,their extraction ratios (E_(H)), in both human and mouse hepatocytes.Surprisingly, ARI-083, which has a 2-amino substitution at the1,3,4-oxadiazole moiety, had lower clearance and hepatic extractionparameters than ARI-060, which has a 2-methyl substitution at the 1,3,4oxadiazole moiety. ARI-118 and ARI-120 had even lower values thanARI-083, which is not substituted with halogen.

In the amide series, ARI-004's metabolic profile was improved by fluoroor chloro substitutions at the indole ring, as demonstrated by the lowerclearance and E_(H) value of ARI-049 and ARI-065 in both human and mousehepatocytes. However, in the ester series, only the fluoro substitution(ARI-055) led to improvement in the metabolic profile of ARI-001.

It remains unclear whether halogen substitutions at the indole ringimpact the activity and metabolic profiles of the indole compoundsdescribed herein. Preliminary studies analyzing metabolites of thesecompounds in hepatocytes by high-resolution mass spectrometry identifiedfewer primary metabolites of the indole ring of ARI-002, ARI-087 orARI-143 than expected on the basis of what has typically been observedwith indole metabolism. Moreover, in silico modeling of electronwithdrawing and atomic charge on these molecules did not reveal anythingthat could explain the present in vitro results. These data suggest thatthe class of indole compounds disclosed herein is an entirely new classof molecules with unexpected and previously unknown properties.

Example 155: In Vivo Pharmacokinetic Studies in Rodents

This example describes pharmacokinetic (PK) studies of the variousindole compounds described herein in rats, a rodent species widely usedfor pre-clinical toxicology evaluation. In the present studies, the testcompounds were given to groups of Sprague-Dawley rats (N=3 in eachgroup) intravenously (IV) at 2 mg/kg or orally (PO) at 10 mg/kg. IVdoses were formulated in DMSO, while PO doses were formulated in a 50/50mixture of PEG400 and Tween 80. Blood samples were collected at pre-doseand over a period of 24 hours post-dose. Plasma concentrations of theindole compounds were determined by HPLC. Table 7 below shows theresults of the PK study on select indole compounds.

TABLE 7 PK Studies IV (2 mg/kg) PO (10 mg/kg) Compound Plasma % ofHepatisc ID AUClast AUCinf Clearance Blood Flow AUClast AUCinf F %ARI-001 173 174 12,147 289 1 4 0.4 ARI-004 240 256 7,945 189 430 43133.6 Ketone Series ARI-002 1940 1940 1,090 26 1,060 1,060 10.9 ARI-067145 147 14,700 350 26 36 3.5 ARI-087 838 873 3,510 84 858 859 19.7ARI-143 2,810 2,820 810 19 2,280 2,720 19.3 ARI-149 4,390 4,390 542 131,480 1,490 6.8 Oxadiazole Series ARI-030 3,920 4,120 1,180 28 180 1830.9 ARI-031 480 483 4,330 103 144 152 6.3 ARI-083 1,360 NA 1,877 45 68NA 1.0 ARI-118 2,790 2,890 713 17 32 33 0.2 *AUClast: area under theplasma drug concentration versus time curve from time zero to time oflast measurable concentration. AUCinf: area under the plasma drugconcentration versus time curve from time zero to infinity. F:bioavailability (systemic availability of the administered dose; F % =100 × (PO AUCinf × equivalent IV DOSE)/(IV AUCinf × equivalent PODose)).

In the ketone series, the PK data show that for IV administration,ARI-002 had lower plasma clearance, as well as higher AUCinf, comparedto ARI-001. ARI-087 had 3.2 times higher plasma clearance than ARI-002,and an IV AUCinf that was 45% of that of ARI-002. ARI-143 exhibitedplasma clearance that was 74% of ARI-002 and 1.5 times higher IV AUCinfthan ARI-002. Among all the ketone compounds tested, ARI-149 had thelowest plasma clearance (50% of that of ARI-002) and the highest IVAUCinf (2.3 times higher than ARI-002).

For oral administration, ARI-149, while exhibiting a PO AUCinf that wasabout 1.4 times higher than that of ARI-002, exhibited an absolute oralbioavailability that was only 62% of ARI-002. These oral exposure dataand absolute bioavailability values are consistent with ARI-149's highIV AUCinf. ARI-087 exhibited a PO AUCinf that was 81% of that of ARI-002and absolute oral bioavailability that was 1.8 times higher thanARI-002. Surprisingly, ARI-143, which had IV PK profiles comparable tothose of ARI-149, exhibited much better oral PK profiles than ARI-149:unlike ARI-149, ARI-143 had significantly higher PO AUCinf (2.6 timeshigher) and higher absolute oral bioavailability (1.8 times higher) thanARI-002.

Notably, although ketone compounds having 5-fluoro substitution(ARI-087) and 5-chloro substitution (ARI-067) at the indole ring hadcomparable metabolic profiles in vitro, the former substitution wasshown to accord significantly lower plasma clearance and much betteroral bioavailability than the latter substitution in the in vivo PKstudies, where compound solubility and absorption in the animals werelikely additional influential factors.

In the oxadiazole series, the PK studies in rats show that the indolecompounds with an oxadiazole moiety, i.e., ARI-030, ARI-031, ARI-083,and ARI-118, had improved IV PK profiles compared to ARI-001, ARI-002,and ARI-004. A separate PK study performed in mice on ARI-030 andARI-031 confirms the improvement accorded by the oxadiazole moiety overARI-001 and ARI-002 (data not shown). Among the oxadiazole derivativestested in rats, ARI-030, ARI-083, and ARI-118 displayed better IV PKprofiles than ARI-031, with ARI-118 having the best profile.

Example 156: Anti-Tumor Activity of the Indole Compounds in AnimalModels

This example describes in vivo studies that evaluated the anti-cancerefficacy of the disclosed indole compounds in syngeneic mouse tumormodels. Mice implanted subcutaneously with four types of cancer cellswere treated with test indole compounds or vehicle controls as describedbelow.

Materials and Methods

Cell Culture

A monolayer culture of tumor cells was maintained in vitro in DMEM orRPMI1640 medium supplemented with 10% fetal bovine serum at 37° C. in anatmosphere of 5% CO₂. Cells in exponential growth phase were harvestedand quantitated by cell counter before tumor inoculation. The cell linesused are described in the table below.

Cell Line Cancer Type Culture Medium EMT-6 breast cancer DMEM + 10% FBSPan02 pancreatic cancer RPMI1640 + 10% FBS LL/2 lung cancer DMEM + 10%FBS A20 B cell lymphoma RPMI1640 + 10% FBSSubcutaneous Syngeneic Mouse Tumor Models

Four subcutaneous syngeneic mouse tumor models were generated byinoculating female BALB/C or C57BL/6 mice with cancer cells at theirright lower or front flank as detailed in the table below:

Cell line Cell Number Inoculation site MouseStrain EMT-6 5 × 10⁵ rightlower flank BALB/C Pan02 3 × 10⁶ right front flank C57BL/6 LL/2 3 × 10⁵right lower flank C57BL/6 A20 5 × 10⁵ right lower flank BALB/C

Each mouse was inoculated subcutaneously with tumor cells in 0.1 mL ofPBS. Treatments were started when the mean tumor size reachedapproximately 80-120 mm³ (around 100 mm³). The administration of theindole compounds and the animal number in each study group are shown inthe study design. The date of tumor cell inoculation was denoted as day0.

Formulation of Indole Compounds

The indole compounds were dissolved in DMSO at the final concentrationof 26.7 mg/ml and stored at room temperature.

Study Design

Randomization of animals was started when the mean tumor size reachedapproximately 90 mm³ to form the mouse study groups. The randomizationwas performed based on “Matched distribution” method using themulti-task method (StudyDirector™ software, version3.1.399.19)/randomized block design. The mouse groups (ten in eachgroup) were treated with vehicle (DMSO) or the indole compounds at adose of 40 mg/kg by i.p. injection, QD for 28 days or longer.

Observation and Data Collection

After tumor cell inoculation, the mice were checked daily for morbidityand mortality. During routine monitoring, the mice were checked fortumor growth and any effects of the treatment on behavior such asmobility, food and water consumption, body weight gain/loss (bodyweights were measured twice per week after randomization), eye/hairmatting, and any other abnormalities. Mortality and observed clinicalsigns were recorded for individual mice in detail.

Tumor volumes were measured twice per week in two dimensions using acaliper, and the volume was expressed in mm³ using the formula:V=(L×W×W)/2,where V is tumor volume, L is tumor length (the longest tumor dimension)and W is tumor width (the longest tumor dimension perpendicular to L).Dosing as well as tumor and body weight measurements was conducted in aLaminar Flow Cabinet. The body weights and tumor volumes were measuredby using StudyDirector™ software (version 3.1.399.19).Dosing Holiday

A dosing holiday was given to the mice after one measurement of bodyweight loss (BWL)>30%. The length of the dosing holiday was long enoughfor the body weight to recover to BWL<30%, at which time the treatmentwas resumed. The mice were not fed any additional nutrient supplementduring the dosing holiday.

Experimental Termination

Tumor growth inhibition percentage (TGI %) is an indicator for antitumoractivity of a drug compound, and expressed as:TGI (%)=100×(1−T/C),where T and C are the mean tumor volume (or weight) of the treated andcontrol groups, respectively, on a given day. Statistical analysis ofthe difference in mean tumor volume (MTV) among the groups was conductedusing the data collected on the day when the MTV of the vehicle groupreached the humane endpoints, so that TGI could be derived for all ormost mice enrolled in the study.

The body weight of all animals was monitored throughout the study andanimals were euthanized if they lost over 20% of their body weightrelative to the weight at the start of the study and could not recoverwithin 72 hour.

All of the mice in the same group would be sacrificed when the MTVreached 2000 mm³, or an individual mouse would be sacrificed when thetumor volume reached 3000 mm³.

To deter cannibalization, any animal exhibiting an ulcerated or necrotictumor would be separated immediately and singly housed and monitoreddaily before the animal was euthanized or until tumor regression wascomplete. Mouse with tumor ulceration of approximately 25% or greater onthe surface of the tumor would be euthanized.

Statistical Analysis

For comparison between two groups, a Student's t-test was performed. Alldata were analyzed using SPSS 18.0 and/or GraphPad Prism 5.0. P<0.05 wasconsidered statistically significant.

Results

In vivo studies were performed in the above-described syngeneic mousetumor models to evaluate the anti-tumor activity of ARI-001, ARI-002,ARI-004; ARI-002 derivatives ARI-087, ARI-140, ARI-142, ARI-143, andARI-149; and oxa- or thia-diazole derivatives ARI-090, ARI-118, ARI-120,ARI-145, ARI-146, and ARI-148.

In Studies 1 and 3, the anti-tumor activity of ARI-001 in parallel withARI-002 at 160 mg/kg (mpk), and the anti-tumor activity of ARI-087 inparallel with ARI-002 at 40 mpk were assessed using the EMT-6, Pan02,A20, and LL/2 models. Because EMT-6 provides a fast growing model thatenables relatively quick differentiation of performance betweencompounds, this syngeneic mouse tumor model was chosen for the otherstudies. In Study 2, the anti-tumor activity of ARI-002 was comparedwith that of ARI-004 at 10, 40, and 80 mpk. In Study 4, the anti-tumoractivity of ARI-087 was compared with that of ARI-140. In Study 5, theanti-tumor activity of ARI-087 was evaluated in parallel with ARI-143and ARI-149 at 40 mpk. Table 8 summarizes the tumor growth inhibition(TGI) data collected on the indicated days post tumor inoculation. Thevehicle arm was terminated on the indicated days (D), when the vehiclecontrol mice reached the humane endpoints.

TABLE 8 TGI Data of in vivo Studies Compound ID EMT-6 Pan02 A20 LL/2Study 1 ARI-001 (160 mpk)   53.0% D27 74.2% D28   54.5% D26 65.1% D28ARI-002 (160 mpk)   54.6% D27 77.9% D28   44.7% D26 69.0% D28 Study 2ARI-001 (160 mpk)   75.1% D27 ARI-002 (10 mpk)   14.9% D27 N/D* N/D N/D(40 mpk)   33.3% D27 (80 mpk)   54.6% D27 ARI-004 (10 mpk) −38.2% D27N/D N/D N/D (40 mpk)    0.3% D27 (80 mpk)   15.8% D27 Study 3 ARI-002(40 mpk)   41.4% D27 64.9% D60    9.7% D28 19.9% D38 ARI-087 (40 mpk)  56.7% D27 64.9% D60   20.9% D28 23.3% D38 ARI-030 (40 mpk)   21.9% D2723.5% D60  −0.8% D28  8.4% D28 ARI-083 (40 mpk)   21.2% D27  2.7% D60    22% D28 24.0% D28 Study 4 ARI-087 (40 mpk)   29.5% D28 N/D N/D N/DARI-140 (40 mpk)   30.6% D28 N/D N/D N/D ARI-118 (40 mpk)   54.5% D28N/D N/D N/D Study 5 ARI-087 (40 mpk)   42.2% D30 N/D N/D N/D ARI-143 (40mpk)   65.9% D30 N/D N/D N/D ARI-149 (40 mpk)   42.7% D30 N/D N/D N/DARI-120 (40 mpk)   27.2% D30 N/D N/D N/D ARI-145 (40 mpk)   10.5% D30N/D N/D N/D ARI-146 (40 mpk)   23.2% D30 N/D N/D N/D ARI-148 (40 mpk)   4.8% D30 N/D N/D N/D Study 6 ARI-087 (40 mpk)   52.8% D26 N/D N/D N/DARI-056 (40 mpk)   34.3% D26 N/D N/D N/D ARI-090 (40 mpk)   30.1% D26N/D N/D N/D *N/D: not determined.

The TGI data of Study 2 show that ARI-002 at 80 mpk had comparableefficacy as ARI-001 at 160 mpk. The TGI data of Study 3 show that inthree of the tumor models (breast, lung, and lymphoma), ARI-087exhibited better tumor inhibitory activity than parent compound ARI-002,while it exhibited similar tumor inhibitory activity compared to ARI-002in the pancreatic cancer model. See the TGI Table above and FIGS. 60A-D.Due to its high potency, ARI-087 was selected as a positive control forsubsequent in vivo anti-tumor studies.

Studies 4 and 5, together with unshown data, demonstrate that otherketone derivatives, ARI-140, ARI-142, and ARI-149 were similar toARI-087 in anti-tumor potency. See the TGI Table above and FIGS. 61 and62. The data also shows that in the EMT-6 model, ARI-087 delayed tumorgrowth and prolonged survival: at day 27 in the same study as ARI-002,the ARI-087 arm had 6 out of 10 animals with tumor volumes <1000 mm³, ascompared to the ARI-002 arm, which had only 3 out of 10 animals withtumor volumes <1000 mm³.

Study 5 further shows that ARI-143 was the most potent ketone derivativein the EMT-6 tumor model. See the TGI Table above and FIG. 63. ARI-143was shown to delay tumor growth and prolong survival; and it led tocomplete tumor regression (CR) in 2 out of 10 animals by day 51, both ofwhich remained tumor-free, as compared to the ARI-087 arm, which did nothave any animal in CR. The superior anti-tumor efficacy of ARI-143confirms the compound's properties exhibited in in vitro potency andmetabolic assays, as well as suggested by the compound's in vivo PKdata.

Further studies were performed to evaluate the anti-tumor activity ofoxa- or thia-diazole derivatives ARI-030, ARI-056, ARI-083, ARI-090,ARI-118, ARI-120, ARI-145, ARI-146, and ARI-148 as compared to ARI-002and ARI-087. The TGI data of Studies 3, 5, and 6 show that in the EMT-6model, ARI-120, ARI-145, ARI-146, ARI-148, ARI-056, and ARI-090 showedless anti-tumor potency than ARI-087. See the TGI Table above.

Notably, the remaining oxadiazole derivative tested, ARI-118, exhibitedsuperior anti-tumor activity than ARI-087. See the TGI Table above andFIG. 64. ARI-118 was shown to delay tumor growth and prolong survival;and it led to complete tumor regression (CR) in 1 out of 10 animals byday 46, as compared to the ARI-087 arm in the same study, which did notresult in a CR until day 81.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present invention shall have the meanings that arecommonly understood by those of ordinary skill in the art. Exemplarymethods and materials are described below, although methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention. In case ofconflict, the present specification, including definitions, willcontrol. Generally, nomenclature used in connection with, and techniquesof, cell and tissue culture, molecular biology, immunology,microbiology, genetics, analytical chemistry, synthetic organicchemistry, medicinal and pharmaceutical chemistry, and protein andnucleic acid chemistry and hybridization described herein are thosewell-known and commonly used in the art. Enzymatic reactions andpurification techniques are performed according to manufacturer'sspecifications, as commonly accomplished in the art or as describedherein. Further, unless otherwise required by context, singular termsshall include pluralities and plural terms shall include the singular.Throughout this specification and embodiments, the words “have” and“comprise,” or variations such as “has,” “having,” “comprises,” or“comprising,” will be understood to imply the inclusion of a statedinteger or group of integers but not the exclusion of any other integeror group of integers. All publications and other references mentionedherein are incorporated by reference in their entirety. Although anumber of documents are cited herein, this citation does not constitutean admission that any of these documents forms part of the commongeneral knowledge in the art.

Other embodiments of the present disclosure are within the scope of thefollowing claims.

The invention claimed is:
 1. A compound of Structural Formula 8, or anenantiomer, diastereomer, or pharmaceutically acceptable salt thereof,

wherein R₂ is selected from the group consisting of heteroaryl and

wherein R_(2a) is H, C1-C6 alkyl, hydroxy, thioalkoxy (—S— alkyl), cyano(—CN), or amino; and R₄, R₅, R₆, and R₇, are each, independently,selected from the group consisting of hydrogen and halo.
 2. The compoundof claim 1, wherein R₂ is heteroaryl.
 3. The compound of claim 2,wherein the heteroaryl is oxadiazolyl or thiadiazolyl, optionallysubstituted with one or more hydroxyl, amino, nitro, cyano, C1-C6 alkyl,or C1-C6 alkyl amino.
 4. The compound of claim 1, wherein R₂ is—C(O)—R_(2a), and wherein Rea is C1-C6 alkyl.
 5. The compound of claim1, wherein at least one of R₄, R₅, R₆, and R₇ is F, Cl or Br, and theothers of R₄, R₅, R₆, and R₇ are hydrogen.
 6. The compound of claim 1,wherein R₅ is F or Cl, and R₄, R₆, and R₇ are hydrogen.
 7. The compoundof claim 1, wherein R₆ is F or Cl, and R₄, R₅, and R₇ are hydrogen. 8.The compound of claim 1, wherein R₇ is F or Cl, and R₄, R₅, and R₆ arehydrogen.
 9. The compound of claim 1, wherein R₅ and R₆ are F or Cl, andR₄ and R₇ are hydrogen.
 10. The compound of claim 1, wherein R₅ and R₇are F or Cl, and R₄ and R₆ are hydrogen.
 11. The compound of claim 1,wherein R₆ and R₇ are F or Cl, and R₄ and R₅ are hydrogen.
 12. Thecompound of claim 1, wherein each of R₄, R₅, R₆ and R₇ is hydrogen. 13.The compound of claim 1, which is selected from any one of the compoundsin the following table, or an enantiomer, diastereomer, orpharmaceutically acceptable salt thereof: ARI-# Structural Formula 002

031

060

083

087

090

118

120

140

143

145

146

148

149

150


14. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.